From gut to kidney: Transporting and metabolizing calcineurin-inhibitors in solid organ transplantation

International Journal of Pharmaceutics 452 (2013) 14–35

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From gut to kidney: Transporting and metabolizing calcineurin-inhibitors in solid organ transplantation Noël Knops a,b,∗ , Elena Levtchenko a,b , Bert van den Heuvel b , Dirk Kuypers c a b c

Department of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Belgium Laboratory for Pediatrics, Department of Development & Regeneration, KU Leuven, Belgium Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Belgium

a r t i c l e

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Article history: Received 8 March 2013 Received in revised form 8 May 2013 Accepted 10 May 2013 Available online 24 May 2013 Keywords: Calcineurin-inhibitors Tacrolimus Cyclosporine CYP3A5 CYP3A4 P glycoprotein

a b s t r a c t Since their introduction circa 35 years ago, calcineurin-inhibitors (CNI) have become the cornerstone of immunosuppressive therapy in solid organ transplantation. However, CNI’s possess a narrow therapeutic index with potential severe consequences of drug under- or overexposure. This demands a meticulous policy of Therapeutic Drug Monitoring (TDM) to optimize outcome. In clinical practice optimal dosing is difficult to achieve due to important inter- and intraindividual variation in CNI pharmacokinetics. A complex and often interdependent set of factors appears relevant in determining drug exposure. These include recipient characteristics such as age, race, body composition, organ function, and food intake, but also graft-related characteristics such as: size, donor-age, and time after transplantation can be important. Fundamental (in vitro) and clinical studies have pointed out the intrinsic relation between the aforementioned variables and the functional capacity of enzymes and transporters involved in CNI metabolism, primarily located in intestine, liver and kidney. Commonly occurring polymorphisms in genes responsible for CNI metabolism (CYP3A4, CYP3A5, CYP3A7, PXR, POR, ABCB1 (P-gp) and possibly UGT) are able to explain an important part of interindividual variability. In particular, a highly prevalent SNP in CYP3A5 has proven to be an important determinant of CNI dose requirements and drug-dose-interactions. In addition, a discrepancy in genotype between graft and receptor has to be taken into account. Furthermore, common phenomena in solid organ transplantation such as inflammation, ischemia- reperfusion injury, graft function, co-medication, altered food intake and intestinal motility can have a differential effect on the expression enzymes and transporters involved in CNI metabolism. Notwithstanding the built-up knowledge, predicting individual CNI pharmacokinetics and dose requirements on the basis of current clinical and experimental data remains a challenge. © 2013 Elsevier B.V. All rights reserved.

1. Introduction The necessity to exert long-term suppression of the immune system to prevent allograft rejection was apparent from the time the first experiments in transplantation were conducted. The first successful kidney transplantation in humans avoided

Abbreviations: CNI, calcineurin-inihibitors; CsA, cyclosporine A; CNIT, CNI related nephrotoxicity; CN, calcineurin; NFAT, nuclear factor of activated T cells; Vd , volume of distribution; AUC, area under the concentration curve; BCS, Biopharmaceutics Classification System; DHA, Docosahexaenoic acid; SNP, single nucleotide polymorphism; TDM, therapeutic drug monitoring; CMPF, 3-carboxy-4-methyl-5propyl-2-furan-propanoic acid; IRI, ischemia-reperfusion-injury. ∗ Corresponding author at: Department of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. Tel.: +32 16 343827; fax: +32 16 343842. E-mail addresses: [email protected], [email protected] (N. Knops). 0378-5173/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ijpharm.2013.05.033

this problem by using a graft from an HLA identical twin brother (Merrill et al., 1956).The technical feasibility of the surgical concept encouraged trials with total body irradiation as a means to achieve decreased alloreactivity in recipients of an HLA non-identical graft. Sadly, however, these patients succumbed to the complications of radiation-induced bone marrow depression. The advent of 6-mercaptopurine, an orally administered purine analog, that proved effective in prolonging graft survival (Calne, 1960; Murray et al., 1963; Zukoski et al., 1960), gave birth to modern immunosuppressive therapy and revolutionized the field of solid organ transplantation. A second leap forward improving 1-year graft survival from circa 60 to 80% came after the introduction of the calcineurin inhibitor (CNI) cyclosporine A (CsA) in the late 70’searly 80’s. Later adjuvant immunosuppressive agents (mycophenolate mofetil, mTOR inhibitors (=Proliferation Signal Inhibitors), anti-IL-2 receptor blocking monoclonal antibodies) have delivered a modest further improvement in outcome, but could not replace the central position of CNI’s in standard immunosuppressive

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regimes. Depending on the type of organ transplanted current 5-year graft survival is approximately 50% for lung, pancreas and small bowel, 70% for heart and liver, and almost 80% for kidney transplantation (Cai and Terasaki, 2010; Mazariegos et al., 2010; Opelz and Dohler, 2009; Opelz et al., 2010). With acute rejection now being a less important problem, attention has shifted toward designing a “tailored immunosuppressive maintenance therapy”, aimed at optimization of drug efficacy and the prevention of unintended and possible deleterious side effects in the individual recipient. For a “perfect fit” this entails a fundamental knowledge of the individual characteristics of the recipient and its graft in relation to the pharmacodynamic and -kinetic properties of the separate agents and their combination. In general, CNI’s are difficult drugs to use: (1) They demonstrate a narrow therapeutic index with important acute clinical toxicity when blood levels exceed the desired range; (2) there is a poor correlation between the administered dose and the resultant blood concentration and (3) important intra- and inter-individual variation in pharmacokinetics exists. Consequently, therapeutic drug monitoring (or concentration controlled dosing), guiding CNI treatment is currently regarded as a vital part of clinical practice in solid organ transplantation. Unfortunately, long term CNI usage has proven to be complicated by the development of nephrotoxicity, leading to the demise of kidney function in both renal and non-renal solid organ transplantation. CNI related nephrotoxicity (CNIT) is an important factor in long-term allograft failure in recipients of a renal graft but is also associated with the development of chronic kidney disease in non-renal graft recipients. The underlying mechanisms are not known, but variation in genotype and phenotype of enzymes and transporters involved in CNI metabolism appears important in CNIT development. This review will discuss the currently marketed CNI formulations together with their pharmacokinetic profile and shall then focus on the different actors in CNI disposition in relation to the optimization of CNI therapy after solid organ transplantation. 2. Calcineurin inhibitors The first calcineurin inhibitor (CNI) to be used in transplantation was cyclosporin A (CsA). It was introduced in renal transplantation in the late 1970s (Calne et al., 1979; Calne et al., 1978). Tacrolimus (FK-506) was introduced in 1987 and since then has gradually replaced CsA due to a generally perceived milder range of side effects and possible better efficacy (Webster et al., 2005). Recently, a phase 2b study in low risk renal transplant patients was published demonstrating equal short term efficacy of tacrolimus versus a new CNI named voclosporin (Busque et al., 2011). Voclosporin (ISA247) is an engineered variant from cyclosporine A, designed with the aim to limit CsA related (nephro)toxicity. Since the limited information and experience regarding this new agent we will focus in this review on CsA and tacrolimus. 3. Pharmacodynamics Calcineurin (CN) is a heterodimer consisting of a 57 to 59 kDa catalytic subunit (CnA) and a 19 kDa regulatory subunit (CnB), and is one of four classes of cytoplasmatic serine/threonine phosphatases that have been characterized in mammalian cells(termed PPase 1, 2A, 2B (=calcineurin) and 2C). The name “calcineurin” was derived from its calcium binding properties and original isolation from neuronal tissue (Klee et al., 1979). A Fe3+ -Zn2+ metal cluster in subunit A is required for phosphatase activity, which is reversibly inhibited by oxidation of the iron ion(King and Huang, 1984). Unlike PPase 1 and 2A, the phospatase activity of calcineurin and PPase 2C is calciumand calmodulin dependent (Fruman et al., 1996). T-cell receptor binding gives rise to an increase in intracellular Ca2+, this then

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activates CN resulting in the dephosphorylation of the DNA binding factor: “Nuclear Factor of Activated T cells” (NFAT), depicted in Fig. 1. After dephosphorylation, NFAT is able to translocate to the nucleus and bind to the IL-2 promotor region initiating transcription and T cell activation (Muller and Rao, 2010). However, CN is not T lymphocyte specific and is present in essentially all tissues, albeit in different isoforms and with different functions (Rusnak and Mertz, 2000). Furthermore, the denominator “NFAT” refers to a family of transcription factors important in the immune response, but members of the NFAT family are also involved in many aspects of vertebrate development including cardiac muscle and the brain (Wu et al., 2007). NFAT1 to 4 are the primary substrates of CN, but CN is also involved in the dephosphorylation of other proteins (such as synapsin 1, synaptopodin and neuromodulin) (Descazeaud et al., 2012; Musson et al., 2011). CsA and tacrolimus have a chemically distinct structure (Fig. 2), but share the capability to form intracellular complexes with specific immunophilin-binding proteins (respectively cyclophylin and FKBP12). These immunosuppressant-immunophilin complexes (IS-IP) interact (gain of function model) with a hydrophobic groove at the junction between the A and B subunit of CN. Since this region is also involved in the interaction with CN substrates, binding of the IS-IP complex to CN will inhibit phosphatase activity and NFAT signaling (Rodriguez et al., 2009; Siekierka et al., 1989). 4. Cyclosporine A Cyclosporine A is a small cyclic polypeptide consisting of eleven amino acids, first extracted from the fungus Tolypocladium inflatum at the Sandoz laboratories in 1970. It’s immunosuppressive effect in animals was described first by Borel and coworkers in 1977 (Borel et al., 1977). The apparent lack of a cytostatic effect in comparison to the prevalent immunosuppressive methods at that time encouraged further studies in humans. Only one year later Calne published the results of their drug based regimen including cyclosporine in 6 recipients of a cadaveric kidney (Calne et al., 1978). However, initial enthusiasm was dampened by significant side effects and morbidity. These problems were later attributed to the initial high doses and after lowering the dose substantially, CsA proved very efficient in improving outcome in solid organ transplantation. Other indications for CsA include: rheumatoid arthritis, uveitis, nephrotic syndrome, psoriasis and bone marrow transplantation. 4.1. CsA pharmacokinetics Cyclosporine A is most commonly delivered in capsules. It is also available as a suspension for oral administration, intravenous solution and an emulsion for ophthalmic application, and is produced by different pharmaceutical companies. There are considerable differences in the pharmacokinetic profiles between the different oral formulations and this has to be taken into account, especially when switching from one to another (Dunn et al., 2001). CsA shows very poor solubility in water and therefore the original formulation brought on the market by Sandoz (now Novartis) was oil-based (brand name: Sandimmune® ). The oral bioavailability varied considerably, ranging from 1 to 89%, with a mean value of 30% (Kapturczak et al., 2004). In addition the olive oil formulation demonstrated a decrease in bioavailability with the concurrent intake of food with a high fat content. In the mid-nineties a new formulation was introduced, designed to form a microemulsion in contact with water (Neoral® ; Novartis). After release from the capsule this formulation has the ability to self-emulsify and create micelles that are absorbed in the small bowel. It is less dependent on bile for absorption and the effect of the concomitant intake of fatty food is largely eliminated (Dunn et al., 2001; Wu and Benet, 2005).

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Fig. 1. A schematic model of T cell activation after stimulation of the T cell receptor via calcineurin and the mechanism of immunosuppression by calcineurin inhibitors. Abbreviations: TCR: T cell receptor; CN: calcineurin; NFAT: nuclear factor of activated T cells; CNI: calcineurin inhibitor; IP: immunophilin; P: phosphate group; IL-2: Interleukin 2 gene.

Currently, most physicians prefer the microemulsion because of its better bioavailability and less intra- and interindividual variation. Therefore, we will primarily focus on the pharmacokinetics of the microemulsion. Notwithstanding, the bioavailability of the microemulsion is still variable between 10 and 89% with an average of circa 40% depending on the populations studied (Mueller et al., 1994). After ingestion maximum CsA blood concentrations are reached within circa 1.5–2 h. In studies in renal transplantation, rheumatoid arthritis and psoriasis patients, the mean AUC was approximately 20% to 50% larger, and the peak blood concentration (Cmax ) was approximately 40% to 106% higher following administration of the

microemulsion compared to the oil-based formulation. Circa 50% of the absorbed fraction is readily metabolized in the intestines, and 8% is lost due to hepatic first pass metabolism (Kolars et al., 1991; Wu et al., 1995). CsA biotransformation takes place through CYP3A isoenzymes into more than 30 metabolites (Christians and Sewing, 1993). The primary metabolites: AM1, AM9 and AM4N, and some secondary and tertiary metabolites, AM1c, AM19 and AM1c9, are abundantly present in blood, urine and bile. CYP3A4 oxidizes CsA at multiple positions (1 MeBmt, 4 MeLeu, 9 MeLeu, etc.) and is known to convert CsA into three major primary metabolites (AM1, AM9 and AM4N). CYP3A5 preferentially attacks at amino acid 9 (9 MeLeu) and metabolizes CsA to only one primary metabolite (AM9) (Dai et al.,

Fig. 2. Chemical structure tacrolimus and cyclosporine A (ref: http://www.emolecules.com/).

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2004). Although in vitro and animal studies have shown that CsA metabolites, and in particular AM1, can inhibit T cell function, it is not clear whether they exert a clinically significant effect in humans (Ozbay et al., 2007). The volume of distribution of CsA lies between 3 and 5 L/kg in solid organ recipients. Circa 33–47% is present in plasma, 4–9% in lymphocytes, 4–12% in granulocytes, and 41–58% in erythrocytes. Circa 90–98% of cyclosporine in plasma is bound to plasma proteins, primarily lipoproteins (85–90%) (Dunn et al., 2001). The half-life is approximately 8.4 h, with a range from 6 to 27 h. Blood clearance in adults after renal or hepatic transplantation is approximately 5–7 mL/min/kg. Clearance in prepubertal children is circa 25% higher (Fanta et al., 2007). CsA elimination occurs primarily via bile and only 6% of the original dose is excreted via urine (0.1% unchanged). Renal failure has no significant influence on clearance parameters. The first trials with CsA in solid organ transplantation in humans already illustrated the importance of adequate dosing of CsA. Later clinical studies indicated that a better control of CsA exposure resulted in a lower incidence of acute or chronic rejection and a better graft survival with lower health care costs (Kahan et al., 1996; Kahan et al., 2000; Lindholm and Kahan, 1993). CsA AUC0–4 was found to be a good predictor for the risk of acute rejection and drug-related nephrotoxicity (Clase et al., 2002; Mahalati et al., 1999). However, the assessment of a 4-h AUC is impractical in routine practice. The more convenient CsA trough level (C0 ) does not have a good correlation with total exposure. However, the CsA level 2 h postdose (C2 ) proved to be a reasonable alternative to AUC0–4 . Moreover, in vitro data have shown that the maximal inhibition of CN and IL-2 production in leukocytes occurs at 2 h after administration (Halloran et al., 1999; Sindhi et al., 2000). Large-scale clinical trials in both liver and kidney transplantation suggested lower acute rejection rates and good tolerability when using C2 based CsA monitoring over C0 , leading to a European Concensus statement in 2005 (Nashan et al., 2005). However, the quality of the studies was poor and an meta-analysis by Knight et al. could not detect a clinical benefit of C2 monitoring (Knight and Morris, 2007). On an individual basis, the measurement of additional time points in the first weeks after transplantation and occasional routine assessment of a CsA PK profile is advised in order to distinguish patients with aberrant (delayed) absorption from patients with an inadequate dose. 5. Tacrolimus Tacrolimus (FK-506) is a 23-membered macrolide lactone, isolated from the fermentation broth of Streptomyces tsukubaensis, and its immunosuppressive ability was first described in 1987 (Kino et al., 1987). It is one of the most successful immunosuppressive drugs in transplantation and over recent years the majority of solid organ recipients are treated with tacrolimus. 5.1. Tacrolimus pharmacokinetics The standard tacrolimus formulation is a capsule containing a solid dispersion with lactose monohydrate for oral administration and was initially marketed under the name Prograf® by Astellas Pharma. In addition, a prolonged-release hard capsule (Advagraf® , Astellas Pharma) was introduced in 2007 (Silva et al., 2007). Furthermore, intravenous and topical preparations (the latter for the treatment of atopic dermatitis) are available and tacrolimus granules have been developed aimed at pediatric liver transplantation. After oral administration absorption takes place in the small bowel. The maximum blood concentration is reached 1–3 h after ingestion. The oral bioavailability is low, around 20% of the

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administered dose reaches the circulation, with a large interindividual variation, range from 4 to 93% (Venkataramanan et al., 1995). Tacrolimus is a lipophilic molecule and ingestion together with a fatty meal decreases absorption. Furthermore, absorption appears to be limited by dissolution rate and alterations in gut motility after transplantation may explain intra-individual variability in uptake (Wallemacq and Verbeeck, 2001). Before entering the systemic circulation, extensive metabolism takes place in the intestinal mucosa and liver cells under the influence of the CYP3A isoenzymes, contributing to the low oral bioavailability. CYP3A initiates O-demethylation of the tacrolimus molecule, destabilizing the macrolide ring and leading to further secondary and tertiary metabolites. Since it is recognized that the ring structure constitutes the binding region of the FK binding protein, destabilizing the ring structure will have important influence on the immunosuppressive activity of tacrolimus metabolites (Galat, 1993; Iwasaki et al., 1995; Lhoest et al., 1998; Lhoest et al., 1995). Until now 9 metabolites of tacrolimus have been identified. The 13-O desmethyl metabolite (designated M-1) is the major metabolite, but retains little or no immunosuppressive activity. The 31-O desmethyl metabolite (M-2) was found equipotent to tacrolimus and demonstrated, together with the 15-O-desmethyl, 15–31 O-di-desmethyl, and the C19-C20 epoxide metabolite, significant immunosuppressive potency (Iwasaki et al., 1995; Iwasaki et al., 1993b; Lhoest et al., 1998). However in a clinical setting the concentrations of these active metabolites were below the detection threshold and it seems likely that they do not contribute significantly to the immunosuppressive efficacy (Mancinelli et al., 2001). In analogy with CsA, tacrolimus is predominantly metabolized by the CYP3A4 and CYP3A5 enzymes. The intrinsic clearance of tacrolimus for CYP3A5 is approximately 2-fold higher than for CYP3A4 (Dai et al., 2006). CYP3A5 catalyses the formation of four primary metabolites (M1, M2, M3 and M6). Whereas, it is uncertain if CYP3A4 also produces the hydroxyl metabolite (M6) (Bader et al., 2000). Circa 95% of tacrolimus that enters the systemic circulation is bound to erythrocytes, driven by the abundance of FK binding proteins in these cells. The other ∼5% remains primarily in the plasma compartment and is bound to non-albumin proteins (Nagase et al., 1994). Consequently, the volume of distribution (Vd ) based on whole blood concentrations is low compared to Vd based on plasma concentrations (circa 0.5–1.4 L/kg versus 30 L/kg) (Wallemacq and Verbeeck, 2001). Animal studies demonstrated a wide distribution of tacrolimus in different tissue, in particular lung, spleen, kidney, heart, pancreas, brain, muscle and liver (Wijnen et al., 1991). The mean terminal elimination half-life after a single dose of tacrolimus is 44 h and therefore steady state will not be reached until several days (Moller et al., 1999). Elimination predominantly happens via extensive metabolism followed by biliary excretion. Less than 0.5% of the unchanged drug is detectable in the feces and urine and 3% of the total administered dose can be retrieved from the urine (Moller et al., 1999). Phase I trials have demonstrated that Advagraf® has a delayed tmax (2–3 h) with a lower Cmax versus Prograf® (after conversion on a 1 mg:1 mg basis), consistent with its extended-release characteristics. Trough level (Cmin ) and AUC24 are similar, albeit generally lower (median 10%, range −15% to −35%) in comparison to the twice-daily formulation. Clinical studies reported 5–40% lower tacrolimus exposure (in particular in the early post-transplant period) after 1:1 conversion, which eventually led to a higher daily dose of the extended release formulation to achieve similar trough levels (Barraclough et al., 2011). As for CsA it is recommended to guide tacrolimus dosing on blood levels. In clinical practice trough levels are used, which were found to have an acceptable correlation (r > 0.9) with the AUC12 (Bottiger et al., 2002; Kuypers et al., 2004; Wong et al., 2000). Renal insufficiency and mild hepatic dysfunction does

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not have a significant effect on tacrolimus clearance. However, severe cholestasis can induce a substantial reduction in tacrolimus clearance and thus increase exposure and drug toxicity (Gonschior et al., 1996; Winkler et al., 1994).

6. Predicting CNI pharmacokinetics according to the BCS model The Biopharmaceutics Classification System (BCS) was originally developed to allow prediction of in vivo pharmacokinetic performance of drugs from measurements of permeability and solubility (Food and Drug Administration, 2000). Both tacrolimus and CsA are highly lipophilic and therefore demonstrate high permeability, but low aqueous solubility and are designated as Class II drugs according to the BCS. High permeability will allow easy permeation into cell membranes, eliminating the need for uptake transporters. However, low solubility will limit further drug distribution into the cell, preventing saturation of the efflux transporters. Consequently, efflux transporters should have a relatively large effect on the oral bioavailability of class II drugs. Furthermore, the relatively lower intracellular concentration of these compounds is less likely to saturate enzymes involved in drug metabolism. For this reason common phenomena such as the presence of specific drug inducers/inhibitors or genetic variation with an effect on enzymes and transporters can have an important effect on class II drug disposition. In many situations the importance of the extent of metabolization will prevail over permeability. This notion led to a proposal to amend the original BCS classification by laying more emphasis on the extent of drug metabolism and rename it as the Biopharmaceutics Drug Disposition Classification System (BDDCS) (Benet, 2009a; Wu and Benet, 2005). Food can increase or decrease the extent and rate of bioavailability of a certain drug and this can be predicted based on the BDDCS class. Especially for class II drugs with passive membrane permeation such as tacrolimus and CsA, high fat meals were hypothesized to increase bioavailability, due to inhibition of intestinal efflux transporters and additional solubilization in the lumen (Wu and Benet, 2005). However, the time to reach peak concentrations could also lengthen due to a delay in gastric emptying after a fatty meal. Clinical studies confirmed delayed peak concentrations, but surprisingly demonstrated a decrease in tacrolimus AUC0 –12 after a fatty meal (Bekersky et al., 2001a,b). Similar findings were made in trials with the extended release formulation (Barraclough et al., 2011). Studies on the effect of the dietary fat contents on the kinetics of the oil-based CsA formulation are somewhat conflicting (Gupta et al., 1990; Lindholm et al., 1990). Although oral bioavailability appears increased after a high fat diet, a concurrent increase in CsA clearance eventually resulted in a similar exposure (Tan et al., 1995). Interestingly this increase in CsA clearance in response to a fatty meal appears not related to the route of administration since similar observations were made after intravenous CsA administration in healthy subjects (Gupta and Benet, 1990). This could imply an increase in hepatic clearance of CNI’s after a fatty meal, possibly through inhibition of P-gp in the hepatocytes (Wu and Benet, 2005). After the “leading” role for the intestine in oral drug disposition, we have arrived at the liver and kidney. In contrast to the relative unimportance of uptake transporters for Class 2 drug bioavailability, they can play a major role in hepatic and renal elimination. Metabolism is regarded as the most important route for the elimination of the highly permeable BDDCS Class 1 and 2 drugs, whereas renal and biliary excretion of the unchanged drug is the major route for the poorly permeable Class 3 and 4 drugs. The available data on the role of specific enzymes and transporters on CNI absorption,

distribution, metabolism and elimination is discussed elsewhere in this paper. Despite extensive knowledge on the physical properties of a certain drug and the enzymes and transporters involved in its disposition, it remains challenging to predict the pharmacokinetic behavior in individual subjects. In vitro studies performed in “isolated models” such as microsomal preparations or cell lines derived from different organs or even isolated liver, kidney or intestinal perfusion chambers can be used to analyze the pharmacokinetic behavior of a compound within its compartment but will fail to reflect the complex interplay from gut to kidney in “in vivo” drug disposition. Therefore, computer models like the Advanced Dissolution, Absorption and Metabolism (ADAM) model or the Segmental-Segregated Flow Model have been developed with the aim to incorporate the specific role of different tissue segments, blood flow and regional drug metabolism. Their discussion falls beyond the scope of this review, but are described excellently in other papers (Cong et al., 2000; Darwich et al., 2010; Jamei et al., 2009).

7. CNI’s in the Gut The process of drug metabolism is initiated directly after administration. Degradation in the gut by intestinal fluids, microbial flora and enzymatic activity in the microvilli can be of great importance for the first pass metabolism of oral drugs before hepatic passage. A schematic overview of CNI passage via epithelial cells of the intestine, liver and kidney is depicted in Fig. 3. In the intestinal lumen there is a wide range of hydrolytic and phase II enzymes present that are also able to contribute to the metabolism of a variety of drugs. These include acyltransferases, glutathione S-transferases and UDP glucuronosyltransferases (Krishna and Klotz, 1994). Furthermore, the physicochemical properties of the molecule such as lipophilicity and solubility can interact with food constituents and affect absorption as discussed earlier. An important feature of the gut is the large absorptive surface area covered by villus tip enterocytes that provides a sea of opportunity for enzyme-drug interaction, facilitating substantial first pass metabolism (Wacher et al., 2001). Intracellular drug metabolism primarily occurs via CYP3A enzymes, which constitute the majority of CYP450 enzyme content in enterocytes (70%). Identified CYPs in the human intestine include CYP1A1, CYP2C810, CYP2D6, CYP2E1, CYP3A4, CYP3A5 and CYP3A7. The relative CYP3A protein content is highest in the proximal small intestine and exceeds hepatic concentrations (Canaparo et al., 2007b; von Richter et al., 2004; Yang et al., 2004). CYP3A expression decreases downstream in the gut (Paine et al., 1997). CYP3A4 is present in the relatively high concentrations, although with a highly variable interindividual expression level (Canaparo et al., 2007b; Koch et al., 2002; Lown et al., 1994; Wacher et al., 2001). CYP3A4 has a very broad substrate specificity and is involved in the phase I metabolism of about 50% of currently used drugs (Kivisto et al., 2004). Paine et al. found intestinal CYP3A5 protein expression in only in 4 out of 20 subjects and concluded that for most individuals CYP3A5 plays a minor role in first pass metabolism. However the microsomal preparations from these “expressors” demonstrated an important contribution by CYP3A5 to intestinal drug metabolism in this subgroup (Paine et al., 1997). A later study by von Richter et al. found that quantifiable intestinal CYP3A5 expression was related to carriership of the CYP3A5*1 allele. In these subjects the liver homogenate demonstrated a slightly higher CYP3A5 concentration compared to the intestinal samples (von Richter et al., 2004). Intestinal CYP3A activity can be influenced by food constituents. Docosahexaenoic acid (DHA) is one of the polyunsaturated fatty acids (PUFAs) classified as an omega-3 fatty acid and is present

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Fig. 3. Route map of CNI’s and CNI metabolites through enterocyte, hepatocyte and proximal tubular cell with the tissue specific cellular localization of enzymes and transporters involved in CNI metabolism. (M: CNI metabolite). In the intestines the CNI will enter the enterocyte by passive diffusion at the apical cell surface. There it can encounter P-gp and as a result be effluxed back into the intestinal lumen before (or after metabolization) by CYP3A (and possibly UGT). The drug then has a new opportunity to re-enter the cell, allowing more metabolites to be formed and less of the unchanged drug to pass toward the basolateral surface. The pregnane X receptor (PXR) and P450 oxidoreductase (POR) are involved in functional CYP3A and ABCB1/P-gp expression. In the hepatocyte and proximal tubular cell the drug enters from the basolateral side and is exposed to metabolization prior to efflux at the apical surface. As a result less metabolites are formed and more unchanged drug traverses the membrane.

in fatty fish and mother’s milk. A study combining an in vitro and in vivo animal model demonstrated that orally administered DHA inhibits intestinal CYP3A mediated CsA metabolism, and thus enhances bioavailability (Hirunpanich et al., 2006). Active luminal secretion of the parent drug and metabolites is recognized as an alternative mechanism affecting drug bioavailability. P-glycoprotein 1 (P-gp, also known as multidrug resistance protein 1 (Mdr1) or ATP-binding cassette sub-family B member 1 (ABCB1)) is a glycoprotein that acts as a multidrug efflux pump. P-gp is extensively distributed and expressed in enterocytes, hepatocytes, renal proximal tubular cells and capillary endothelial cells. P-gp expression was demonstrated throughout the gut. In situ perfusion of murine intestinal segments, found decreasing permeability values for P-gp substrates from duodenum to ileum, in accordance with a measured increase in P-gp expression levels (Gonzalez-Alvarez et al., 2007). Conflicting data exist considering intestinal P-gp expression in humans. One paper described an increase in expression from the proximal toward the distal part (Mouly and Paine, 2003), but others could not confirm these findings (Canaparo et al., 2007a). CYP3A and the multidrug efflux pump, P-gp, have an important overlap in their substrate specificities, which allows CYP3A to have repeated contact with the substrate and its metabolites after extrusion by P-gp and subsequent reabsorption. It was postulated that the synergy between CYP3A and P-gp constitutes an integral part of the intestinal defence system, protecting the body against harmful xenobiotics through the inhibition of their systemic penetration by intense metabolization and drug extrusion (Kivisto et al., 2004). The concerted effects of both drug metabolism and transport will have a major impact on oral drug bioaviability and variation.

The importance of intestinal metabolism on CNI bioavailability was first clearly demonstrated by Kolars et al. In their seminal study they instilled CsA into the small bowel of two patients during the anhepatic phase of liver transplantation. Analysis of portal venous blood found that between 25 and 50% of the drug had already been metabolized, suggesting that intestinal metabolism could be more important than hepatic metabolism in determining cyclosporine bioavailability (Kolars et al., 1991). CYP3A4 was then identified as the enzyme primarily responsible for intestinal CsA metabolism and the magnitude of first pass metabolism could be further enhanced by specific inducers or inhibitors of CYP3A4 (Kolars et al., 1992; Preuner et al., 1998; Wu et al., 1995). Tacrolimus metabolism in human intestinal microsomes was first described by Lampen et al. (1995). With the use of intestinal microsomal preparations derived from 14 subjects they demonstrated a broad interindividual variation in CYP3A-mediated tarolimus metabolism. They performed further experiments to study tacrolimus metabolism and transport using pig gut in an Ussing chamber. The metabolite formation was highest in the duodenum and declined in the order duodenum > jejunum > ileum > colon > stomach. More than 90% of metabolites re-entered the gut lumen and only small amounts passed into the serosa chamber, indicative of a significant efflux activity in the enterocytes. After 4 h, only 2% of the administered drug was detected in the serosal chamber, demonstrating the high intestinal capacity for first pass tacrolimus metabolism (Lampen et al., 1996). The differential expression of enzymes and transporters according to the localization along the gut can be of importance for variation in oral bioavailability during a state of altered intestinal motility. It might also affect drug exposure after conversion to an

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extended release formulation, which are presumed to be absorbed further downstream than the twice-daily formulations. With regard to intestinal P-gp expression in relation to CNI metabolism less data exist. Lown et al. assessed CYP3A4 and P-gp protein levels in duodenal biopsies obtained from renal transplant recipients and concluded that 17–30% of variation in CsA pharmacokinetics could be explained by inter-individual differences in intestinal P-gp concentrations (Lown et al., 1997). Matsuda found an inverse correlation between the tacrolimus concentration/dose (C/D) ratio and the intestinal mRNA level of ABCB1. They assessed intestinal ABCB1 mRNA in the upper jejunum in 46 recipients of a living donor liver graft in relation to tacrolimus trough levels and dose. After classifying the subjects according ABCB1 mRNA expression, they found that the tacrolimus dose in the “high expressors” was approximately twofold higher than in the “low expressors”, irrespective of known genetic variations of ABCB1 (Masuda et al., 2005). In addition, animal studies have demonstrated that P-gp expression levels dramatically increased in the intestine in response to treatment with CsA (Jette et al., 1996).

8. CNI’s in the liver In the liver, the absorbed drug enters the hepatocytes from the sinusoidal blood. There it is either metabolized and transported back into the blood, or eliminated via the bile. P-gp is located on the opposite canalicular membrane of hepatocytes (Fig. 3). This entails that in contrast with the gut, where the transporter precedes the enzyme, in the liver drug confronts CYP3A before P-gp efflux. An elegant study which made use of isolated perfused rat livers illustrated this principle and demonstrated that hepatic P-gp inhibition resulted in a prolonged exposure of tacrolimus to CYP3A in the hepatocyte and therefore increased tacrolimus metabolism (Wu and Benet, 2003). Quantitatively CYP3A4 is the major CYP3A enzyme in the liver and accounted for 95% of CYP3A mRNA in a set of 63 human livers (Koch et al., 2002). An earlier study with human liver microsomes demonstrated that CYP3A4 was the most important enzyme for tacrolimus metabolism. However, specific and complete inhibition of CYP3A4 could not completely abolish its metabolism. CYP2D6 was also found capable of tacrolimus metabolism, but appears to play only a minor role (<10%) (Karanam et al., 1994). In analogy with the intestine, hepatic CYP3A5 activity has been demonstrated to be of importance for drug metabolism only in individuals with a high expression profile of this enzyme. In this particular subpopulation CYP3A5 contributes circa 5–50% to the total hepatic CYP3A mRNA pool (King et al., 2003; Koch et al., 2002). Both CsA and tacrolimus were demonstrated to competitively inhibit CYP3A in human liver microsomes. In vivo experiments in renal allograft recipients indicate that CsA is a stronger CYP3A4 inhibitor than tacrolimus (de Jonge et al., 2011a). In vitro experiments in specific CYP3A4- and CYP3A5-expressing insect-derived microsomes revealed that tacrolimus inhibited both the A4 and A5 isoenzyme, whereas CsA only inhibited CYP3A4 (Amundsen et al., 2012). Furthermore, the rate of tacrolimus metabolism could be significantly increased in rat liver microsomes through CYP3A induction via dexamethasone treatment (Prasad et al., 1997). Together with MRP2, P-gp was found the major drug transporter expressed in the liver, with expression levels 3.5 fold higher than in the small intestine (Tucker et al., 2012). MRP2 does not appear to play an important role in CNI transport; we found only one report that suggested that CsA transport may be competitively inhibited by pravastatin via MRP2 (Kato et al., 2010). However, it is well recognized that CsA (but not tacrolimus) can inhibit MRP2

function (Kobayashi et al., 2004). A considerable inter-individual difference in the hepatic expression of P-gp exists, in which only age demonstrated a significant positive relation with hepatic expression level (discussed later). Animal studies have demonstrated that prolonged treatment with CsA resulted in induction of hepatic P-gp in a dose dependent manner (Bai et al., 2001). The effect of longterm tacrolimus exposure on hepatic P-gp expression is not known, but studies with renal and endothelial cells could not demonstrate significant upregulation of P-gp under pharmacological tacrolimus concentrations (Hauser et al., 1998; Kochi et al., 1999).

9. CNI’s in the kidney CNI metabolism in the kidney is of lesser importance for CNI disposition. This is evident from the aforementioned studies, which describe the major influence of hepatic and intestinal factors on CNI pharmacokinetics and the relative unimportance of renal function in CNI dosing. Nonetheless, the same enzymes and transporters involved in CNI metabolism elsewhere are present in the proximal tubular cells of the kidney as well. In addition, some of the most important side effects of CNI’s take place in the kidney and can lead to acute and chronic renal failure. This is a serious issue, most prominent in the field of renal transplantation, but also present in other disciplines of transplantation or autoimmune disease, and an important reason to achieve a better understanding of CNI metabolism and disposition in the kidney. Renal drug clearance occurs primarily via direct filtration of the unchanged drug or its metabolites into the urine. However, the drug can also pass via the tubular cells with concomitant metabolism and eventual excretion. In the latter the drug moves from the peritubular capillaries through the basolateral membrane of the tubular cell (Fig. 3). In analogy with the situation in the liver, after passage into the cell the drug is either metabolized by CYP3A and transported back into the blood, or eliminated via transporters located at the brush border into the urine. Following metabolization and excretion in the intestine and liver, less than 3–6% of the initial CNI dosage of respectively tacrolimus or CsA can be detected in the urine (Christians et al., 2002; Dunn et al., 2001). In contrast to the intestine and liver, the CYP3A4 isoform is expressed in only a minority of human kidney samples while CYP3A5 appears to be the major CYP3A enzyme in the human kidney (Dai et al., 2006; Haehner et al., 1996; Koch et al., 2002; Schuetz et al., 1992). Immunohistochemistry demonstrated that CYP3A5 protein was confined to the proximal tubular cells (Bolbrinker et al., 2012). Isolated kidney microsomes that were incubated with CsA were demonstrated to produce only the AM9 metabolite, underlining the importance of CYP3A5-mediated CsA metabolism over CYP3A4 in the kidney (Dai et al., 2004). This domination of CYP3A5 over CYP3A4 is even more pronounced in the aforementioned CYP3A5 expressors. A study in kidney samples from 93 patients revealed that CYP3A5 mRNA expression in kidneys of carriers of the CYP3A5*1 allele was over 18-fold higher than that of homozygous CYP3A5*3 carriers. In accordance kidney microsomes from CYP3A5 expressers generated higher concentrations of tacrolimus metabolites than microsomes from non-expressers (13.5-fold). A recent study in healthy volunteers described a 36% lower urinary tacrolimus clearance in CYP3A5 expressors as compared with nonexpressors. With the help of the pharmocokinetic parameters established in this cohort, the authors developed a semi-physiological model of renal tacrolimus disposition and predicted that tacrolimus exposure in the renal epithelium of CYP3A5 expressors is 53% of that for CYP3A5 nonexpressors, when normalized to blood AUC. These data suggest that intrarenal accumulation of tacrolimus and its metabolites depends on the CYP3A5 genotype of the liver and kidneys (Zheng et al., 2012).

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The proximal tubule cells are equipped with multiple drug transporters localized in the membrane at both sides of the cell and with overlapping substrate specificities. P-gp, was first described as a renal drug transporter in the early 1990s (Tanigawara et al., 1992). It is located on brush border membrane of the proximal tubular cell. It has been demonstrated to facilitate the active renal excretion of drugs such as alkaloids, anthracyclines, steroids, and other hydrophobic organic cations, including the CNI’s (Launay-Vacher et al., 2006; Saeki et al., 1993). The expression of P-gp in normal human kidneys is not known. However, P-gp expression in renal grafts with signs of CNI related nephrotoxicity appears decreased versus grafts without this histological damage (Joy et al., 2005; Naesens et al., 2009). Experimental data suggest that renal P-gp expression can vary in reaction to different (environmental) stimuli. For example, uremic conditions for 48 h reduced P-gp expression in an in vitro model of human proximal tubular cells by 35% (Naud et al., 2011), while expression was significantly increased in cells cultured in the presence of bile acids, 1,25(OH)(2)D(3), platelet activating factor, dexamethasone, or aldosterone (Kneuer et al., 2007; Romiti et al., 2002). Furthermore, animal and in vitro studies have shown that both CsA and tacrolimus at higher concentrations induce renal P-gp expression and function (Hauser et al., 1998; Jette et al., 1996; Liu and Brunner, 2001). 10. Pharmacogenetics As mentioned before, interindividual variability in the expression of the enzymes and transporters involved in CNI metabolism is high and responsible for large differences in CNI dose requirements. Genetic polymorphisms can play a critical role in determining interindividual variation in protein functionality. Indeed, longitudinal and cross-sectional analysis of clinical and genetic co-variables in allograft recipients has identified several single nucleotide polymorphisms (SNPs) in genes encoding for enzymes and transporters, which were associated with differences in dosing, toxicity and drug interactions. There is a constant flow of papers investigating the clinical relevance of genetic variants for the field of organ transplantation; these papers are discussed elaborately elsewhere (Coto et al., 2011; de Jonge and Kuypers, 2008; de Jonge et al., 2009; Rosso Felipe et al., 2009; Staatz et al., 2010a; Staatz et al., 2010b; Zhou et al., 2008). In the following section we will give a survey of the proteins and their underlying genetic variants with possible implications for CNI metabolism (see also Table 1). We will start with the most important SNP for CNI disposition, since it will be regularly referred to in the other paragraphs.

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common CYP3A5*3 allele has sequence variability in intron 3, which involves an A to G transition at position 6986 of the CYP3A5 gene (rs776746) and is responsible for an aberrantly spliced mRNA with a premature stop codon. This splice variant is more unstable and results in a lower amount of CYP3A5 protein expression in subjects homozygous for CYP3A5*3 compared with people carrying at least one CYP3A5*1(Kuehl et al., 2001). The latter are therefore commonly designated as “CYP3A5 expressor” and the former as “non-expressor” while this is not necessarily true. As stated earlier the contribution of CYP3A5 to drug metabolism is important since CYP3A5 can contribute to over 50% of total CYP3A content and the intrinsic CNI clearance capacity of CYP3A5 is approximately twice that of CYP3A4 (Dai et al., 2006; Kamdem et al., 2005). Not surprisingly, clinical studies have indicated that CYP3A5 “expression” results in an estimated 25–40% increase in tacrolimus clearance and 2–3 fold lower dose-corrected trough levels. Therefore, it was suggested to use information on the CYP3A5 genotype in initial drug dosing. Indeed, Thervet et al. demonstrated in a prospective trial involving 280 renal transplant recipients that pretransplant tacrolimus dose adaptation according to CYP3A5 genotype, resulted in more rapid achievement of target C0 and fewer dose modifications (Thervet et al., 2010). In addition, CYP3A5 expressors were found to have less intra-individual variation in PK parameters than non-expressors (Yong Chung et al., 2010). Possibly explained by the fact that in the latter CNI metabolism is more dependent on CYP3A4, an enzyme more sensitive to induction and inhibition. However, one should realize that also within the group of “expressors” a large variation in CNI clearance exists, and that there is a considerable overlap with the non-carriers. Furthermore, TDM demonstrated that CYP3A5*1 carriers can have a different concentration-time profile, resulting in an increased tacrolimus exposure with similar trough levels (Renders et al., 2007). Therefore, it is advised to cautiously use genotyping in dose predictions and perform regular TDM to guide CNI treatment. In contrast with tacrolimus, the effect of the CYP3A5*1 allele on CsA dose requirements is less prominent. CsA metabolite formation appears increased in relation to CYP3A5 expression in preparations of liver and kidney microsomes (Dai et al., 2004). However, several clinical studies were unable to demonstrate an increase CsA dose requirements in CYP3A5 expressors (Bouamar et al., 2011; Staatz et al., 2010a). Most of these studies used single time samples (C0 or C2 levels) as parameter for drug exposure. The few studies that did perform more extensive pharmacokinetic modeling demonstrated lower dose corrected AUC0 –12 in expressors, although the effect of a linkage desequilibrium with the ABCB1 C3435 T SNP was not excluded (see later) (Anglicheau et al., 2004; Min et al., 2004; Yates et al., 2003).

10.1. CYP3A5

10.2. CYP3A4

MacPhee et al. were the first to identify the importance of common genetic variants of the CYP3A5 gene in CNI metabolism. In a group of 180 kidney transplant recipients, patients with at least one CYP3A5*1 allele achieved twofold lower dose-normalized tacrolimus blood concentrations compared with homozygous CYP3A5*3 allele carriers (Macphee et al., 2005). Since then numerous studies, performed in different disciplines of solid organ transplantation, have confirmed the significant impact of the CYP3A5*1 allele on CNI metabolism (reviewed elsewhere (Barry and Levine, 2010; de Jonge and Kuypers, 2008; Rosso Felipe et al., 2009; Staatz et al., 2010a,b)). CYP3A5*1 is the most important functional variant of the CYP3A5 gene. The frequency of the CYP3A5*1 SNP is highly dependent on ethnicity and is present in only a minority of Caucasians (5–15%), Asians (15–35%) and Mexicans (25%). But this allele is present in the majority of people from African descent (45–73%) (Lamba et al., 2002). The more

10.2.1. CYP3A4*1B At least 34 polymorphisms in CYP3A4 have been identified at the moment of writing of this paper (Human CYP Allele Nomenclature Committee, in press). However, none of these SNP’s are reported to result in total loss of CYP3A4 function. The most frequent and most extensively studied SNP involves an A to G transition at position −392 in the promoter region of the CYP3A4 gene (rs2740574), designated CYP3A4*1B (wild-type allele: CYP3A4*1). The frequency of the CYP3A4*1B allele varies according to ethnicity and is present in circa 4% of Caucasians, 55% of African Americans, 9% of Hispanics; but is extremely rare in the Asian population (Ball et al., 1999; Ozawa et al., 2004). The exact effect of this 392A > G transition is not known. A study by Amirimani et al. applied luciferase constructs and suggested that CYP3A4 expression is higher in carriers of the mutant allele due to reduced binding of a transcriptional repressor (Amirimani et al.,

22 Table 1 Genetic determinants in CNI metabolism. (a) (range of) distribution allele frequency according ethnicity (data derived from online NCBI dbSNP and ALFRED database) AA: African-American/Sub Saharan origin; Cauc: Caucasian. (b) Reported effect on CNI metabolism: ↓↓/↑↑: decreased/increased and of clinical importance; ↓/↑: decreased/increased but of uncertain clinical importance; = no significant effect; NA: not available. Localization in cell

Protein

Gene

Genetic variants

Polymorphism

Population allele frequencya

Effect on Tac Metabolismb

Effect on CsA Metabolismb

Cytochrome p450 enzyme

Endoplasmatic reticulum

CYP3A5

CYP3A5

- CYP3A5*1

Wild type

dominant in AA (70–90%)

*1: ↑↑

*1: = /↑

- CYP3A5*3

6986A > G (rs776746)

dominant in Cauc (80–95%)

↓↓ vs *1

=/↓ vs *1

CYP3A4

Chr: 7q21.1 31.8 kbp 15 exons CYP3A4

- CYP3A4*1B

-392A > G (rs2740574)

dominant in AA (55%), rare in other

=/↑

=/↑

Chr: 7q21.1 27.2 kbp 13 exons

- CYP3A*18B

↑

↑

20070T > C; (rs28371759) 20230G > A

circa 1–3% of Chinese ↓

NA

4% (mixed population)

=

↑

40–60% of Cauc. vs 10–15% of AA

NA

=/↑

65–70% Asian, vs 5–15% in AA

NA

NA

50–60% Asian, rare in AA

NA ↑

NA ↑

35–40% Cauc vs 10–20% Chinese

↓

↓

80–90% of AA vs 35–45% Cauc

↑

=

10–40% (mixed)

↑ (in CYP3A5*1)

NA

NA

↑

NA

- CYP3A4*22

2–6% (mixed population)

CYP3A7

CYP3A7

- CYP3A7*1 C

15389C > T (rs35599367) replacement nt -129 to -188

Chr: 7q21-q22.1 30.2 kbp 13 exons ABC transporter protein

Plasma membrane

P-glycoprotein

MDR1 or ABCB1

- ABCB1 3435C > T

Chr: 7q21.12 209,5kbp 29 exons

- ABCB1 1236C > T

(P-gp)

Nuclear Receptors

NAPDH-dependent cytochrome p450 reductase

Nucleus

Membrane of endoplasmatic reticulum

Pregnane X receptor

P450 oxireductase

3435C > T (rs1045642)

- ABCB1 2677G > T/A Above Combined

PXR

- PXR -25385C > T

Chr: 3q12-q13.3 38 kbp 10 exons

- PXR A + 763G

POR

−POR*28 T

1236C > T (rs1128503) 2677G > T/A (rs2032582) -25385C > T (rs3814055) A + 763G (rs6785049) −1508C > T

(rs1057868) Chr: 7q11.2 71.8 kbp 16 exons UDP –glucuronosyltransferases

Endoplasmatic reticulum

UGT1

UGT1A4 Chr: 2q37 54.5 kbp 5 exons

−UGT1A4*4

31C > T

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Superfamily

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2003). Later in vitro and in vivo studies reported contradictory data on the effect of the CYP3A4*1B allele on CYP3A4 catalytic activity (Rodriguez-Antona et al., 2005; Spurdle et al., 2002). Conflicting data exist on the clinical importance of CYP3A4*1B for CNI disposition. First, Hesselink et al. found in a cohort of 64 renal transplant recipients that CYP3A4*1B allele carriers had lower tacrolimus dose-adjusted trough levels compared with homozygous wild-type carriers (Hesselink et al., 2003). These findings would be in accordance with the higher level of CYP3A4 expression, mentioned in the paper by Amrani et al. However, they also demonstrated lower tacrolimus dose-adjusted trough levels in carriers of the CYP3A5*1 allele, but did not look into a possible genetic linkage between these two genotypes. Indeed, later studies confirmed the importance of linkage (50%) of the CYP3A4*1B with the CYP3A5*1 allele. Only one demonstrated an additive effect of CYP3A4*1B on tacrolimus dose requirements one year after transplantation within carriers of CYP3A5*1 (Gervasini et al., 2012; Hesselink et al., 2008; Kuypers et al., 2007). Genetic linkage is a frequent phenomenon within populations and should be taken into account during the analysis of the effect of common polymorphisms in a single gene. The relevance of CYP3A4*1B for CsA metabolism is not established either. Min et al. found lower dose-corrected AUC and higher CsA clearance in homozygous carriers of the mutant allele within a small cohort of 14 healthy volunteers. However, possible linkage with CYP3A5*1 was not excluded, while 11 of 14 subjects were of African American descent, versus 3 Caucasian (Min and Ellingrod, 2003). A study in 151 heart and renal transplant patients found only a subtle and clinically non-relevant increase in the oral clearance of CsA in subjects with the CYP3A4*1B allele, independently of ethnicity or CYP3A5*1 carrier status (Hesselink et al., 2004). Further clinical studies could not confirm an independent and relevant effect of this SNP on CsA dosing (Bouamar et al., 2011; Hesselink et al., 2003). 10.2.2. CYP3A4*18B At the moment of writing this paper CYP3A4*18B is only described in the Asian population with a prevalence of 25–30%. This is a SNP in intron 10 of CYP3A4 and is characterized by G to A substitution at position 20230. It was speculated that this nucleotide mutant might be associated with increased CYP3A4 activity (Fukushima-Uesaka et al., 2004). Indeed, Hu et al. found lower CsA exposure in healthy Chinese subjects homozygous for the CYP3A4*18B genotype versus carriers of the wild type allele (Hu et al., 2007). Short term follow up in a cohort of Chinese renal transplant recipients suggested that subjects with the CYP3A4*18B allele require higher doses of CsA to reach the target levels in the first month after transplantation (Qiu et al., 2008). In this same population strong linkage disequilibrium was detected. Carriers of the CYP3A5*1 allele were more likely to possess the CYP3A4*18B mutant allele than the wild type. Interestingly, additional analysis indicated that combined CYP3A5*1/CYP3A4*18B carriers had a decreased CsA levels when compared to carriers of the CYP3A5*1 or CYP3A4*18B allele separately. A recent paper by Shi et al. evaluated the effects of CYP3A4*18B on single dose tacrolimus PK in 22 healthy Chinese subjects. CYP3A4*18B carriers demonstrated a higher clearance than noncarriers, independent of CYP3A5 genotype (Shi et al., 2011). The importance of CYP3A4*18B for CNI pharmacokinetics in this population and for other ethnicities should be confirmed in further clinical studies. 10.2.3. CYP3A4*22 In a recent study by Wang et al. RNA expression in 76 human liver samples was assessed for a set of 8 marker SNP’s in CYP3A4. A marked allelic expression imbalance in 13% of liver samples was found, fully accounted for by an SNP in intron 6 (rs35599367, C > T),

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designated CYP3A4*22. CYP3A4 mRNA level and enzyme activity in livers with CC genotype were 1.7- and 2.5-fold, respectively, greater than in CT and TT carriers. A subsequent review of 235 patients on a stable dose of statins, showed that carriers of the T allele required a lower statin dose (0.2 to 0.6-fold) than non-T carriers for optimal lipid control (Wang et al., 2011). The CYP3A4*22 SNP could also be of importance in the metabolism of other CYP3A4 substrates. Indeed, this was confirmed in a paper by Elens et al. which described tacrolimus pharmacokinetics according to CYP3A4*22 and other relevant genetic variants in CYP3A4, CYP3A5 and ABCB1 in 185 renal transplant recipients. In this cohort of primarily Caucasian descent they found a minor-allele (T) frequency of 3.5% and no linkage disequilibrium between CYP3A4*22 and either the CYP3A5*3 or CYP3A4*1B allele existed. Further analysis demonstrated that carriers of the T variant allele had an overall 33% lower mean dailydose requirement versus wild type carriers (Elens et al., 2011). The importance of the CYP3A4*22 SNP in tacrolimus and CsA pharmacokinetics will have to be confirmed in further studies and for other ethnicities. 10.3. CYP3A7 The cytochrome P450 3A7 (CYP3A7), constitutes one of the major CYP enzymes in fetal livers, and was initially considered a fetus-specific enzyme. After birth, there is a shift in hepatic CYP3A expression from CYP3A7 to CYP3A4. However, CYP3A7 mRNA has been shown to be expressed in 11–88% of adult livers and intestines, circa 50% of which carry the CYP3A7*1 C allele (Burk et al., 2002; Kuehl et al., 2001; Schuetz et al., 1994). This allele was found to be present in 3% in whites and 6% in African Americans. The CYP3A7*1 C allele is characterized by a replacement of an approximately 60-bp stretch (nt–129 to –188) of the CYP3A7 promoter with a sequence identical to the same region in the CYP3A4 promoter containing 3 transcription binding sites (Kuehl et al., 2001). This region has a higher affinity for pregnane X and constitutively activated receptors resulting in a higher expression of CYP3A7 (Burk et al., 2002). Sim et al. found significant CYP3A7 protein expression in approximately 1 in 10 adult livers, contributing to 9–36% of total CYP3A levels in these livers and therefore possibly relevant in the metabolism of certain CYP3A substrates (Sim et al., 2005). Indeed, CYP3A7 was demonstrated capable to perform 13-O demethylation of tacrolimus in vitro, albeit with a 10–20 fold lower activity than CYP3A4 or CYP3A5 (Kamdem et al., 2005). Few studies describe the effect of CYP3A7*1 C on CNI metabolism. A follow up study on cyclosporine pharmacokinetics in 69 renal and 9 lung transplant recipients during the first year after transplantation revealed 1.4–1.6 higher dose requirements in carriers of the CYP3A7*1 C allele (Crettol et al., 2008). Elens et al. described tacrolimus pharmacokinetics and tissue concentrations in 150 liver transplant recipients during the first week after transplantation. Recipients of a graft derived from a CYP3A7*1 C carrier (n = 12) did not show altered tacrolimus trough levels, dose or tissue levels versus non-carriers (Elens et al., 2007). Unfortunately the recipients were not genotyped in this study. Clearly, more studies are needed, and with regard to the age-dependent shift in expression it would be of interest to look at the effect of CYP3A7 expression and polymorphisms in the pediatric age group. 10.4. ABCB1 P-gp is a member of the ABC (ATP binding cassette) transporter protein family and is encoded by the ABCB1 gene. This transporter protein is an intrinsic membrane protein consisting of more than 1200 amino acids with 2 transmembrane domains and 2 nucleotide-binding domains. P-gp functions as an ATP-dependent efflux pump capable of transporting different

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hydrophobic, cationic, or amphoteric substrates, leading to a reduction of intracellular drug accumulation. The true significance of P-gp for tacrolimus pharmacokinetics was first demonstrated in Mdr1 (murine analog of ABCB1) knock-out mice which had demonstrated a 66% reduction in tacrolimus clearance together with a considerable higher tacrolimus exposure after iv or oral administration (respectively 3 to 8 fold) (Yokogawa et al., 1999). Later in vitro and clinical studies have demonstrated that co-administration of P-gp inhibitors increases bioavailability of P-gp substrates through an increase in absorption. Whereas both CsA and tacrolimus are considered P-gp inhibitors, animal studies have demonstrated that only CsA is a potent inhibitor of P-gp in enterocytes contributing to an increase in oral bioavailability of P-gp substrates, but tacrolimus did not have a significant effect (Saitoh et al., 2006; Wacher et al., 2001). At least 70 SNPs are identified in the ABCB1 gene thus far. None of these results in total loss of P-gp function, although several are associated with inter-patient variability in pharmacokinetics. The most common and extensively studied ABCB1 SNPs include a C to T transition at position 3435 within exon 26 (3435C > T; rs1045642), a C to T transition at position 1236 within exon 12 (1236C > T; rs1128503) and a G to T or A transition at position 2677 within exon 21 (2677G > T/A; rs2032582) of ABCB1. The genetic variation in ABCB1 3435C > T and 1236C > T does not lead to changes in the amino acid sequence of the encoded protein and are so called synonymous SNPs. The possible effects of these synonymous SNPs are thought to result from linkage disequilibrium with a non-synonymous SNP, a decrease in mRNA stability or altered folding and insertion of the protein into the membrane (Kimchi-Sarfaty et al., 2007; Wang et al., 2005). In contrast, the ABCB1 2677G > T/A is a non-synonymous SNP, and results in an altered protein amino acid sequence. Again the presence of the different alleles is highly variable and associated with ethnicity. For example, ABCB1 3435C > T was detected in circa 26% of Caucasians, 20% of Chinese, 27% of Japanese and 5% of African Americans (Miao et al., 2008; Ozawa et al., 2004). The data concerning the functional significance of these SNPs are not unequivocal. Hoffmeyer et al. demonstrated significantly lower ABCB1 mRNA, protein expression and a decreased functional activity of P-gp in duodenal biopsies from subjects homozygous for ABCB1 3435TT (Hoffmeyer et al., 2000). However, Goto et al. could not detect any difference in intestinal ABCB1 mRNA expression in tissue obtained during liver transplantation in 69 subjects. Furthermore, none of the genetic variants in ABCB1 studied showed a significant effect on tacrolimus concentration/dose ratio in the first week after transplantation (Goto et al., 2002). One has to be cautious in the interpretation of these apparently conflicting data, since the underlying population is markedly different, and a state of disease or co-medication could be important in P-gp expression. Interestingly, in the latter study, the C3435 T polymorphism did have a significant correlation with the CYP3A4 mRNA expression level. Intestinal CYP3A4 mRNA was 8-fold lower in those with the 3435 T/T versus 3435 C/C genotype, while CYP3A4 mRNA was 4fold lower in the subjects with the heterozygous 3435 C/T genotype versus the 3435 C/C carriers. This finding is suggestive for linkage disequilibrium between this ABCB1 SNP and genes that regulate expression of CYP3A4. The ABCB1 3435 T variant allele occurs more frequently in conjunction with the CYP3A5*3 allele, but also with the ABCB1 1236C > T and 2677G > T/A SNPs (Anglicheau et al., 2004; Anglicheau et al., 2003; Kim et al., 2001; Kroetz et al., 2003). The combined ABCB1 1236T-2677T- 3435 T (T-T-T) variant haplotype is present in approximately 32% of Caucasians, 5% of African-Americans, 27% of Asian-Americans and 35% of Mexican-Americans (Kroetz et al., 2003). A study in recombinant LLC-PK1 cells demonstrated that ABCB1 variant alleles 3435C > T, 1236C > T and 2677G > T/A, whether present individually or in linkage, significantly minimize

P-glycoprotein activity (0–28% activity) when compared with wildtype activity in vitro (Salama et al., 2006). Although some publications reported higher dose-corrected blood levels in carriers of variant alleles (consistent with possible lower functional activity of P-glycoprotein in the variant genotype) most clinical studies could not demonstrate a significant effect of the ABCB1 3435C > T, 1236C > T and 2677G > T/A SNP on CNI dose requirements after solid organ transplantation (Anglicheau et al., 2004; Bouamar et al., 2011; Crettol et al., 2008; Fredericks et al., 2006; Goto et al., 2002; Haufroid et al., 2004; Tsuchiya et al., 2004). A meta-analysis by Jiang et al. analyzed CsA pharmacokinetics in relation to ABCB1 C3435 T obtained from 1036 individuals derived from 14 separate papers. No major influence of the C3435 T SNP on AUC0 –4 , CL/F, Cmax and C0 could be demonstrated, although AUC0 –12 was lower in subjects with the CC genotype (Jiang et al., 2008). The combination of multiple ABCB1 polymorphisms possibly has more effect on CNI disposition. Indeed several clinical studies in solid organ recipients demonstrate that the presence of 3 or more variant ABCB1 alleles is associated with lower dose adjusted blood concentrations. However, interpretation of these data is difficult due to possible confounding by CYP3A5 genotype in these cohorts (Anglicheau et al., 2003; Chen et al., 2009; Fredericks et al., 2006; Loh et al., 2008; Roy et al., 2006; Wang et al., 2006; Yu et al., 2011). Furthermore, additional inhibition of P-gp by the CNI itself could obscure the effect of genetically determined differences in P-gp function. 10.5. PXR Nuclear receptors regulate metabolic pathways in response to changes in the environment by alterations in gene expression of key metabolic enzymes. Bertilsson et al. identified a human nuclear receptor that is expressed in liver and intestines, and is activated by drugs known to induce human CYP3A expression. Furthermore, this receptor was found to bind to and trans-activate regulatory sequences present in human CYP3A and ABCB1 genes (Bertilsson et al., 1998). Orthologous variants of the receptor were found in different species, all activated by pregnanes, hence the name Pregnane X receptor (PXR) (Moore and Kliewer, 2000). The PXRmediated regulation of expression of cytochrome p450 and P-gp in response to a wide array of endogenous or xenobiotic compounds (e.g. macrocyclic antibacterials, antifungals and corticosteroids) appears a significant and common defense mechanism in living organisms. Polymorphisms in the PXR (or NR1I2) gene are common and are associated with altered regulation of gene transcription. Donor livers with variant PXR alleles (in particular SNPs in the PXR promoter and intron 1) demonstrated altered hepatic expression of PXR, CYP3A4, ABCB1 mRNA and rifampin-inducible CYP3A4 activity in comparison to livers with PXR wild-type alleles (Lamba et al., 2008). However, the clinical relevance of the effect of PXR variants remains uncertain. Benkali et al. applied population pharmacokinetics analysis in a cohort of 32 subjects in the first half year after renal transplantation to assess the effect of the PXR 25385C > T gene (rs3814055) on tacrolimus PK. The variant allele was found to be a significant covariate for apparent oral clearance of tacrolimus, but proved not relevant in the prediction of the individual pharmacokinetic profile (Benkali et al., 2009). Similar findings were published concerning the bioavailability of CsA in a group of pediatric renal transplant patients (Fanta et al., 2010). Press et al. analyzed tacrolimus pharmacokinetics in 31 de-novo renal transplant recipients by nonlinear mixed effects modeling and demonstrated increased clearance in subjects with the PXR 7635A > G allele (rs6785049). However, this SNP explained only 3.5% of variability in tacrolimus exposure (Press et al., 2009). The aforementioned PXR SNP was found not to be relevant for explaining

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variability in CsA pharmacokinetics in a similar cohort (Press et al., 2010). A recent paper on a larger cohort of 158 kidney transplant recipients looked at a set of SNPs in the PXR gene and demonstrated a circa 25% higher tacrolimus dose-adjusted exposure in carriers of the 8055C > T allele (rs2276707) and the aforementioned 7635A > G allele, but not the 25385C > T allele (Barraclough et al., 2012). It is difficult to appreciate the clinical relevance of these findings since PK assessment was performed only at one month after transplantation, and the isolated effect of the PXR SNPs was not presented. In summary, there are indications that genetic variants of the PXR receptor have an influence CNI metabolism, but the clinical relevance is still not clear. It is important to realize that in contrast with the genetic variants of the aforementioned proteins, PXR SNPs would primarily have an effect on the adaptive mechanisms of metabolism and transport in response to a possible harmful compound. This entails that the role of the PXR receptor could be of more importance in the immediate phase after transplantation (with high doses of corticosteroids) or during acute disease in comparison to the steady state during which most studies are performed.

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duodenum, jejunum, ileum and colon tissue. Analyses using a selection of recombinant UGT’s identified UGT2B7 as the most important isoform in relation to CNI metabolism. This was in agreement with the differential hepato-gastrointestinal distribution of CNI glucuronidation activity and the expressional pattern of UGT2B7 mRNA (Strassburg et al., 2001). Laverdiere et al. confirmed the presence of CNI glucuronidation in liver and intestines, but could not reproduce the dominant role for UGT2B7. In contrast they identified UGT1A4 as the major isoform in tacrolimus glucuronidation, and supported this finding by further kinetic studies in the presence of UGT2B7 and UGT1A4 substrates. In addition they studied tacrolimus kinetics in a model of genetically modified human kidney cell lines with common variants of the UGT1A4 gene, and demonstrated that microsomal preparations with overexpression of the UGT1A4*4 variant showed an increased glucuronidation capacity compared to the more common UGT1A4*1, UGT1A4*2 and UGT1A4*3 variants. Unfortunately their available set of liver tissue did not contain UGT1A4*4 carriers, so these data could not be confirmed in hepatic tissue. Therefore it remains to be determined whether genetic variants of the UGT enzymes, and specifically UGT1A4*4, could result in a lower CNI exposure in vivo (Laverdiere et al.).

10.6. POR P450 oxidoreductase (POR) receives two electrons from NADPH and transfers them one at a time to the microsomal cytochrome P450 enzymes. The human POR gene is highly polymorphic. The A503 V sequence variant is found in approximately 28% of human alleles and was demonstrated to variably impair CYP3A4 drug metabolism. POR variants A287P and R457H dramatically reduce CYP3A4 mediated drug metabolism (Miller et al., 2011). De Jonge et al. found that CYP3A5 expressers with the POR*28 T allele had lower tacrolimus trough levels in the first days posttransplantation and reached their target significantly later than homozygous POR*28CC carriers. The POR*28 T allele carriers had significantly higher tacrolimus dose requirements throughout the first year. In CYP3A5 non-expressers the POR*28 SNP did not affect tacrolimus pharmacokinetics (de Jonge et al., 2011b). Similar observations were described after a single dose tacrolimus in a cohort of healthy Chinese volunteers (Zhang et al., 2013). More studies are needed to further validate and explore the influence of genetic variations in the POR gene on CNI metabolism. 10.7. UGT1 The UDP-glucuronosyltransferases (UGT) are a superfamily of proteins localized in the endoplasmic reticulum and are highly expressed in the liver, kidney and throughout the gastrointestinal tract (Ohno and Nakajin, 2009). They play an important part in phase II metabolism. Human UGTs are classified into four families: UGT1, UGT2, UGT3, and UGT8. The most important drugconjugating UGTs belong to UGT1 and UGT2 families. A large variety of UGT isoforms exist and are expressed in a tissue specific pattern. They catalyze a reaction that entails the transfer of a glucuronosyl group to hydrophobic compounds rendering them more watersoluble and facilitating subsequent elimination in bile and urine. Subsequent extracellular transport requires the aid of efflux transporters. Excreted glucuronides in the bile and in the intestinal lumen (from enterocytes) may undergo enterohepatic and enteric recycling, due to luminal ␤-glucuronidase- or bacterial-catalyzed hydrolysis and subsequent intestinal reabsorption of the parent drug (Wu et al., 2011). The importance of glucuronidation in CNI elimination is not well known. But both CsA and tacrolimus glucuronides have been identified in human bile (Christians et al., 1991; Firdaous et al., 1997). Strassburg et al. demonstrated significant cyclosporine and tacrolimus glucuronidation capacity in microsomal preparations derived from human liver, but also from

11. Other genetic determinants Until now the CYP3A5*1 genotype was found the most important genetic determinant of CNI dose requirements. Although its effect clearly is important, it incompletely explains the large variability in dose requirements within populations and has a relatively low allele frequency in Caucasians in comparison to other populations. Further efforts with comprehensive gene analysis in large multi-center cohorts have been attempted to identify additional genetic determinants (for example: rs776746 in CYP3A5, rs2239393 in COMT, rs4253728 in PPARA) that will have to be validated in independent groups. Ironically, in the search for genetic factors one of these studies found that treatment center appeared to be an important factor determining trough levels, but this was partly confounded by genotype and race (Birdwell et al., 2012; Jacobson et al., 2011; Klein et al., 2012). The focus of the aforementioned studies has been toward mutations in the genes closely associated with CNI disposition. However, epigenetic regulation of gene transcription by mechanisms such as DNA methylation, modification of histones and RNA-mediated regulation of gene expression are probably just as important, and responsible for the considerable variation found in genetic homogenous populations. Epigenetic characteristics could be altered by: age, drugs and environmental factors. Indeed in vitro studies have demonstrated that CYP3A4 gene expression may be directly regulated by miRNAs at both the transcriptional and posttranscriptional level or indirectly via downregulation of PXR expression (Pan et al., 2009; Takagi et al., 2008). Cytokines are inherently linked to transplantation and have demonstrated the ability to affect various processes in the living organism, including the expression of genes not directly involved in the immune response. Endotoxin administration to human volunteers increases the serum levels of pro-inflammatory cytokines and decreases CYP-mediated drug metabolism (Shedlofsky et al., 1994). IL-10 is an anti-inflammatory cytokine that regulates Th2 cell differentiation and is associated with transplantation tolerance. One study in healthy subjects showed that the administration of IL-10 downregulated CYP3A activity by 12% (Gorski et al., 2000). Li et al. showed that IL-10 -1082 G/A polymorphisms were associated with tacrolimus pharmacokinetics in Chinese liver transplant patients (Li et al., 2007). A following paper by this group demonstrated that the subgroup of recipients with an allograft derived from a CYP3A5 non-expressors had lower tacrolimus dose requirements if their

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donor had a “low IL-10 production” genotype (−819TT, −592 AA) versus those with a donor with a “high IL-10 production” genotype. This was not found in the CYP3A5 expressors (Zhang et al., 2011a,b). It is uncertain how these data pertain to other populations, but recently a paper from the United States confirmed an association of IL-10 polymorphisms with dose requirements for another CYP3A substrate and immunosuppressant (sirolimus) in a cohort of renal transplant recipients (Sam et al., 2011). Concluding, the variable CYP3A-dependent immunosuppressant disposition of organ transplant patients is also influenced by the intra and interindividual variability of cytokine production, in which the latter again can be determined by genetic variation.

12. Pharmacokinetic CNI-drug interaction The ingestion of a specific drug-drug or drug-food combination can lead to altered pharmacokinetics of one or both of the agents in comparison to the expected behavior when taken individually. This will lead to altered drug concentrations and could lead to an undesired effect. Pharmacokinetic drug interaction can originate anywhere and at any time from the moment the drug enters the gastrointestinal tract until its elimination. Absorption can be influenced through drug-induced processes such as modification of the luminal solubility, formation of non-absorbable complexes, changes in gastrointestinal motility, entero-hepatic circulation, and disturbances of the mucosal barrier. After absorption, alterations in drug metabolism, transport, distribution and excretion can occur. CsA and tacrolimus are distinct molecules, but their metabolism is largely performed via the same enzymes and transporters at the same locations (Benet, 2009b; Karanam et al., 1994; Lampen et al., 1995; Shiraga et al., 1994; Vincent et al., 1992). The most common drug interactions with CsA are therefore also observed with tacrolimus. However, these interactions are not always identical. As stated before, CYP3A enzymes are the most important enzymes for phase I drug metabolism in humans and account for >90% of CNI elimination. Therefore inhibition or induction of this enzymatic complex is regarded as the most common mechanism for CNI drug interactions (Christians et al., 1996; Floren et al., 1997; Garton, 2002; Hebert and Lam, 1999; Iwasaki et al., 1993a; Jones and Morris, 2002; Lampen et al., 1995; Laverdiere et al., 2011; Matsuda et al., 1996; Zhang et al., 2011a,b). Clinically important inhibitors of CYP3A, such as the azole antifungals and calcium channel antagonists have been demonstrated to increase CNI exposure significantly. These drugs are inhibitors or substrates of P-glycoprotein as well. Therefore, the specific contribution of transporter and/or enzyme in the drug-CNI interaction is difficult to determine. Similar mechanisms apply for CNI-food interactions. Specific constituents of green tea, Schisandra Sphenanthera (five flavor berry), and grapefruit juice have been described to raise CNI exposure. There are reports suggesting that this also the case for ginger and tumuric (Egashira et al., 2003; Egashira et al., 2011; Jiang et al., 2010; Liu et al., 2009; Romiti et al., 2004; Vischini et al., 2011; Xin et al., 2011). Concomitant exposure to inducers of CYP3A and P-gp will lead to a decrease in CNI bioavailability. Animal studies have demonstrated that dexamethasone administration results in a decreased CsA and tacrolimus bioavailability, and showed increased expression of Pgp and CYP3A in the intestines and liver (Jin et al., 2006; Lampen et al., 1995; Stiff et al., 1992; Yokogawa et al., 2002). However, the clinical relevance of the effect of corticosteroid co-treatment on CNI disposition remains under debate (Undre and Schafer, 1998). Ishizaki et al. described a patient after bone marrow transplantation whose CsA levels dropped after co-administration with amphotericin B. This was confirmed in an animal model in which a 2 to

3-fold increase in intestinal expression levels of CYP3A and Mdr1 mRNA in response to amphotericin B was demonstrated (Ishizaki et al., 2008). Long-term levothyroxine treatment was found to reduce CsA bioavailability through an increase in duodenal P-gp expression (Jin et al., 2006). A first clue toward pharmacogenetic determination of drug-CNI interaction could be found in a paper published in 2001 that aimed to explore the importance of the route of fluconazole administration on concurrent CNI exposure. In this retrospective study the authors observed a disparate pattern in tacrolimus and CsA levels within their patients. While in most subjects CNI exposure increased markedly after fluconazole administration, the majority of African-American patients did not show any interaction (Mathis et al., 2001). This paper was published before MacPhee first described the importance of genetic variation in CYP3A5 expression in CNI exposure. Indeed, in 2008 we demonstrated that carriers of the CYP3A5*1 allele are less susceptible for fluconazole-induced inhibition of tacrolimus metabolism, resulting in unchanged dosecorrected tacrolimus exposure, in contrast to homozygous carriers of the CYP3A5*3 variant (Kuypers et al., 2008). Similar observations were made regarding ketoconazol and tacrolimus (Chandel et al., 2009). Not all interactions in CNI metabolism can be attributed to CYP3A and P-gp, and herein CsA and tacrolimus appear to differ. CsA decreases CYP2D6 activity by 30% and could thus influence the exposure to CYP2D6 substrates. Tacrolimus does not have this effect (Lecointre et al., 2002; Niwa et al., 2007). CsA increases the plasma concentration of statins by inhibition of organic anion transporting polypeptide 1B1 (OATP1B1) (Ichimaru et al., 2001; Neuvonen et al., 2006; Shitara, 2011). In contrast, tacrolimus was not found to inhibit OATP1B1 (Lemahieu et al., 2005; Shitara et al., 2012). Furthermore, in contrast to tacrolimus, CsA has an effect on mycophenolic acid pharmacokinetics by inhibiting elimination of 7-O-mycophenolic acid glucuronide from the hepatocytes into bile and thus by inhibiting enterohepatic recirculation. The inhibitory mechanism probably involves several biliary transporters, such as MRP2, BCRP and OATP. More information on CNI drug interactions can be found in some well-written papers published elsewhere (Christians et al., 2002; Iwasaki, 2007; Kuypers, 2009; Paterson and Singh, 1997; Zhou et al., 2007).

13. Dosing after organ transplantation The immunosuppressive therapy after solid organ transplantation aims to balance the potential for drug-related toxicity versus the risk of allograft rejection in relation to the time since transplantation. Especially, during the first year after transplantation are frequent dose adjustments, in function of changing target PK levels and the actual attained levels in the allograft recipient, common practice. The period after transplantation is characterized by ischemia- reperfusion injury (IRI), organ dysfunction, concomitant drug usage, alterations in food intake, changes in body composition and a state of inflammation. All of these phenomena have been shown to affect drug disposition. Although most subside in the course after the operation, their effect should be taken into consideration when prescribing different drugs. These non-genetic determinants of CNI clearance are summarized in Table 2. CNI clearance primarily occurs via hepatic clearance and metabolism, in accordance clinical studies have demonstrated that renal impairment does not have an important effect on CNI blood levels and therefore does not require dose adjustment beforehand. However, this observation is primarily based on trough levels and not on complete pharmacokinetic assessment, nor on CNI metabolites. A study by Talaulikar et al. compared CsA PK in patients

N. Knops et al. / International Journal of Pharmaceutics 452 (2013) 14–35 Table 2 Evidence based non-genetic clinical covariates affecting CNI clearance in solid organ transplantation. Non-genetic clinical covariates affecting CNI clearance Recipient

• Age • Bodyweight/surface area • Ethnicity • Diarrhea • Food ingestion • Hepatic dysfunction • Hematocrit • Albumin • Renal failure • Inflammation • Co-medication

Donor

• Delayed graft function/IRI (liver-kidney) • Age (liver) • Graft seize (liver) • Living versus deceased (liver-kidney)

Other

• Time after transplantation

on hemodialysis 5 days pretransplant versus 10–14 days posttransplant, and found similar C0 levels but an increase in C2 levels post kidney transplantation (Talaulikar et al., 2003). Similarly, a retrospective study in 80 patients 2 weeks after renal transplantation demonstrated 35% lower CsA AUC0–4h in recipients of a deceased donor graft versus the recipients of a living donor graft, while there was no difference in trough levels. Because creatinin clearance was worse in the deceased donor group they translated this information to an experimental animal model of renal failure. Again CsA exposure was decreased in the animals after renal failure, which could be attributed to a decrease in enteral drug absorption (Sugioka et al., 2009). Other studies also demonstrated that renal failure can affect the PK profile of metabolites through modulation of drug transporters and enzymes in the gut, liver and kidney (Momper et al., 2010; Okabe et al., 2002; Sun et al., 2006; Sun et al., 2004). This is probably caused by the direct effect of the accumulation of uremic toxins. Uremic serum was found to decrease P-gp and MRP2 protein expression and function in rat enterocytes (Naud et al., 2007; Nolin et al., 2009; Veau et al., 2001). This is in contrast to observations in liver tissue where uremic conditions caused an increase in P-gp and MRP2 expression involved in hepatic drug extrusion and a decrease hepatic OATP2 expression involved in drug absorption (Naud et al., 2008; Nolin et al., 2009). And finally, uremic conditions in renal cells led to a lower expression of drug transporters, among them P-gp, while CYP3A activity was not affected in both an animal model of kidney failure and a human cell line of proximal tubular cells (Naud et al., 2011). Experiments in rat hepatocytes and microsomes identified 3carboxy-4-methyl-5-propyl-2-furan-propanoic acid (CMPF) and indoxyl sulfate out of a set of uremic toxins capable of modifying drug metabolism and transporters (Sun et al., 2004). The removal of uremic toxins through hemodialysis has been demonstrated to result in an acute improvement in hepatic CYP3A activity (Nolin et al., 2006). According to the clinical data, the net effect of this regional differential expression, should result in an overall decrease in CNI exposure during uremic conditions. However, in vivo studies with other CYP3A and P-gp substrates administered in ESRD patients demonstrated an increase in the exposure of certain probes (primarily due to a decrease in hepatic clearance), while the exposure to others remained unchanged (Nolin et al., 2009; Sun et al., 2010). Apparently predictions of drug exposure during uremia based upon the sole expression levels of transporters are not reliable and other substrate specific factors might play a role. More information on the effect of renal disease on drug metabolism and transport can be found elsewhere (Nolin et al., 2008; Sun et al., 2006).

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In addition, the volume of distribution of many drugs is increased in patients with renal failure, probably through a decreased protein binding or alterations in body composition. The uremic toxin CMPF was also demonstrated to inhibit drug-albumin binding (Sun et al., 2006). Furthermore, patients with renal failure may be subject to accumulation of metabolites in addition to the original molecule, which can result in unexpected pharmacologic activity and toxicity (Matzke et al., 2011). A study from the mid-nineties found no difference in tacrolimus metabolite concentrations between renal and liver transplant patients. However, a subgroup of patients with an impaired liver function demonstrated increased levels of tacrolimus and its second-generation metabolites such as didemethyl and didemethylhydroxy tacrolimus (Gonschior et al., 1996). The effect of inflammation and cytokines secretion on the pharmacokinetic behavior of drugs has been reviewed elsewhere (Zidek et al., 2009). Cytochrome P450 enzymes are downregulated by tumor necrosis factor (TNF)-␣, IL-1␤, IL-6, IL-10 and IL-18 (Chaluvadi et al., 2009; Jover et al., 2002; Kalsotra et al., 2007; Nyagode et al., 2010). P-gp is activated by IFN-␥ (Dixit et al., 2005; Heemskerk et al., 2010) whereas TNF-␣, IL-1, IL-2, IL-4 and IL-6 attenuate P-gp activity (Belliard et al., 2004; Belliard et al., 2002; Sukhai et al., 2001). One in vitro study found that IFN-␥ enhanced P-gp activity and thus reduced CsA uptake in human intestinal cells (Dixit et al., 2005). This is in accordance with the clinical findings from a cohort of 155 liver transplant recipients which demonstrated that subjects with higher IL-18 and IFN-␥ serum levels had lower tacrolimus concentration/dose ratios (Li et al., 2012). Furthermore, there are publications demonstrating the influence of IL-10 and of polymorphisms in the IL-10 gene on tacrolimus PK, discussed earlier (Li et al., 2007; Sam et al., 2011; Zhang et al., 2011a,b). However, the true influence of cytokine variability on CNI pharmacokinetics after transplantation has not been established thus far. Ischemia-reperfusion (IRI) is common in the early phase after organ transplantation, and known to affect drug disposition. An animal study revealed that in the first phase of recovery after intestinal IRI the enterocyte expression of P-gp increased by two-fold (in combination with a decrease in absorption rate of tacrolimus). Parallel immunohistochemistry showed P-gp localization in the crypt area at 6 h after reperfusion, and after 24 h at the apical surface of enterocytes (Omae et al., 2005). Remarkably, Ikemura et al. demonstrated that hepatic IRI decreased CsA exposure through an increased expression of CYP3A and P-gp in the upper part of the small intestine (Ikemura et al., 2009). Animal experiments aimed at the confirmed an increase in intestinal P-gp expression after hepatic failure but surprisingly revealed a decrease in P-gp activity. This may be explained by the presence of endogenous P-gp inhibitors in the plasma during hepatic failure (Yumoto et al., 2003). We looked into the effect of delayed (renal) graft function (DGF) due to IRI on tacrolimus requirements and, in contrast with the data from hepatic failure, found higher initial mean CNI values with lower dose requirements in the first week after transplantation. This could be explained by a possible effect of both uremia and IRI on metabolism and transport in the intestine and liver. The presence of at least one CYP3A5*1 allele seemed to attenuate the effect of DGF on initial mean tacrolimus exposure, suggesting that recipients expressing CYP3A5 would be at a lower risk for the inhibitory effects of DGF on tacrolimus clearance (Kuypers et al., 2010). Indeed, a recent paper described a decrease in hepatic CYP3A activity in critically ill patients at risk of acute kidney injury assessed by midazolam elimination. In line with our previous findings additional analyses suggested that this effect is diminished in CYP3A5 expressors (Kirwan et al., 2012), The intrinsic properties of a graft potentially involved in drug metabolism can exert an important effect on CNI pharmacokinetics; this is especially true in liver and intestinal transplantation. In

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the immediate period after transplantation the organ is expected to recover from the consequences of perioperative handling, IRI, metabolic derangements and potential drug toxicity. In liver transplantation initial drug metabolism will shift from primarily intestinal to a combination of liver and intestine, with a concurrent increase in metabolic capacity. Furthermore, physical properties such as donor age, relative size of the organ in comparison to the acceptor, graft perfusion, patency of connections with the native digestive system and possible diversions can affect drug PK. This is illustrated in a report by Shimomura et al. that describes two patients with markedly increased tacrolimus requirements in the first months after living donor liver transplantation. Dose requirements only decreased after restoring intestinal bile drainage and thus improving tacrolimus absorption (Shimomura et al., 2008). Additional changes in intestinal motility and diet after transplantation might have contributed to this phenomenon. Goto et al. demonstrated that allograft genotype can significantly influence tacrolimus PK. Recipients of a liver derived from a CYP3A5*1 allele carrier demonstrated increased dose requirement versus recipients of a liver derived from a non-CYP3A5*1 allele carrier (Goto et al., 2004). Uesugi et al. performed stratification of pharmacokinetic data according to donor/recipient CYP3A5 genotype in a mixed pediatric-adult cohort of 204 liver recipients with a follow up of 35 days after transplantation. They found that recipient CYP3A5*1 allele carriers with homozygous CYP3A5*3 donor livers had increased tacrolimus clearance versus CYP3A5*3 allele carriers with CYP3A5*1 donor livers (Uesugi et al., 2006). A more recent report by Ji et al. in 58 living donor liver recipients with a follow up of 4 years could not detect significant differences in long-term tacrolimus dose requirements between the two donor-recipient combinations with a discordant CYP3A5 genotype over. However, they did find a higher dose normalized tacrolimus concentration within the first month in homozygous CYP3A5*3 recipients with a *1 allele graft versus the *1 recipients with a homozygous *3 liver. This suggests a dominance of intestinal tacrolimus metabolism in the first period after liver transplantation while the hepatic graft is recovering from IRI. However the effect of enlarging liver mass after transplantation of a split (reduced) liver from a living donor cannot be ruled out (Ji et al., 2012). As mentioned earlier, the dosage of CNI’s has to be adjusted over time according to changing exposure target levels in the treatment protocol. However, the dose needed to reach the desired levels of individual drug exposure also appears to change after transplantation. Data from the MO2ART trial in which CsA dose was determined by the C2 level, demonstrated that CsA bioavailability increases in the first 3 months post-transplant and remains similar thereafter until the end of the first year (Buchler et al., 2006). In contrast the observed C0 levels for a given exposure in this study decreased after 3 months reflecting an increase in CsA clearance. Others have observed a significant decrease in the time to achieve Cmax in patients receiving CsA during the first year after renal transplantation (International Neoral Renal Transplantation, 2002). As a consequence, C0 monitoring may progressively underestimate CsA exposure during the first year post-kidney transplant. Tacrolimus dose requirements appear to change after renal transplantation in a similar manner. Interestingly, this appears to be dependent on CYP3A4 and CYP3A5 genotype. Our follow-up study in 95 renal transplant recipients showed a substantial increase in dose-corrected tacrolimus exposure over 5 years in subjects carrying the CYP3A4*1/CYP3A5*3 genotype (Kuypers et al., 2007). While dose requirements did not change in subjects carrying CYP3A4*1/CYP3A5*1 or CYP3A4*1B/CYP3A5*1 genotype. These findings suggest downregulation of CYP3A activity over time, for which carriers of the CYP3A5*1 allele appear less susceptible. In children the dose requirements per kg bodyweight to attain desired blood concentrations are approximately 2.7 fold higher

for patients under 5 years and 1.9 fold higher for patients aged 5 to 12 years when compared to older patients (Claeys et al., 2010; Ferraris et al., 2011; Montini et al., 2006; Naesens et al., 2008). However, the intrinsic metabolic capacity of enzymes during lifetime appears similar. A study comparing hepatic microsomal drug metabolism between adults and children (age: 0.5–9 years) found no absolute differences in CYP3A activity (Blanco et al., 2000). But, age-related differences in expression of enzymes or transporters might play an important role. Fetal hepatic CYP3A4 was reported to be weak, followed by a rise after birth and reaching 30–40% of the adult activity after one month (Lacroix et al., 1997). Similarly, fetal livers did not express P-gp protein, but this could be detected from the age of 1–3 months (Schuetz et al., 1995). A study in 59 duodenal biopsies derived from children aged 1 month to 17 years demonstrated an increase in CYP3A protein staining after the age of 6 months together with high CYP3A4 and CYP3A5 mRNA levels in the first year of life, and decreasing levels of expression thereafter. P-gp was detected at all ages, and was located on the apical surface of enterocytes. In children aged less than 3 years, additional staining was located on a limited upper part of the basolateral cell surface (Fakhoury et al., 2005). Taking the available data on the ontogeny of CYP3A4 and P-gp together we expect, in contrast to the previously mentioned clinical data, relatively higher CNI bioavailability in children and consequently lower dose requirements. Thus, other factors besides differences in functional expression of transporters and enzymes might be of importance in determining increased dose requirements in children compared to adults. One of these factors can be the method used to correct for differences in body dimensions. In children the development of liver mass (LM) lags behind that of bodyweight but is almost identical to that of body surface area (BSA). Thus, children have a greater LM/BW ratio than adults. The BW-normalized clearance for drugs whose metabolism is dominated by enzymes such as CYP3A4, shows significantly negative correlations with age during childhood. In contrast the LM- or BSA-normalized clearances of these drugs are independent of age. This phenomenon results in the perception of an augmented clearance and higher dose requirements when drug dose is normalized for bodyweight in the pediatric age group. BSA-based dosing will probably better reflect the agerelated differences in dose requirements (Kanamori et al., 2002). Other possible factors contributing to altered dose requirement in children versus adults include differences in intestinal transit time and length, body composition (affecting Vd ), protein binding, body metabolism and organ function (Bartelink et al., 2006; Kearns et al., 2003). Clearly the field of pediatric drug disposition needs further studies. Further aging involves the steadily decrease in the functional reserve of our organs. In accordance, first pass metabolism is expected to decrease because of a decline in the absorptive capacity of the gut and a reduction in liver mass and perfusion. In addition body composition changes with age, with an increase in fat and a reduction in body water. Consequently lipophilic drugs will have an increased volume of distribution (Kuypers, 2009; Shi and Klotz, 2011). Therefore aging could result in a higher bioavailability and decreased drug clearance of drugs like CNI’s. Indeed, renal transplant recipients older than 64 years were demonstrated to have considerable lower CNI requirements versus younger patients, irrespective of genotype (Falck et al., 2008; Jacobson et al., 2012). Several studies show reduced clearance of other CYP3A substrates in the elderly. These were reviewed elsewhere (Cotreau et al., 2005). It is not known whether an additional change in the expression of transporters and enzymes are of importance in the elderly. Lown et al. found no association between age and intestinal CYP3A or PgP expression in kidney transplant patients. However, the age of

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subjects in this cohort only ranged from 23 to 67 years (Lown et al., 1997).

14. Conclusion and future directions Circa 35 years have passed since the introduction of CNI based immunosuppressive treatment in solid organ transplantation. No other class of drugs has proven to be as effective as the CNI’s and currently they remain at the basis of pharmaceutical strategies to prevent allograft rejection. During these 35 years of experience it is has become clear that optimal CNI dosing in clinical practice is difficult to achieve due to important inter- and intraindividual variation in CNI pharmacokinetics. A complex and often interdependent set of factors appears relevant in determining drug exposure. This includes recipient characteristics such as age, race, body composition, organ functioning, inflammation, food intake and co-medication, but also graft-related characteristics such as: size, donor-age, graft functioning, IRI, and time since transplantation. Fundamental and clinical studies have pointed out the intrinsic relation with the aforementioned variables and the functional capacity of enzymes and transporters involved in CNI metabolism, primarily located in intestine, liver and kidney. Especially, commonly occurring polymorphisms in the genes responsible for CNI metabolism are able to explain an important part of variability. In addition, a discrepancy in the genotype between graft and receptor has to be taken into account. Unfortunately, despite the great progress made in the field of CNI disposition, it is still not possible to make reliable predictions concerning dose requirements on an individual basis. However, we now have a greater knowledge about the different factors affecting drug exposure after solid organ transplantation. Because of the important relation between CNI exposure and outcome, we advice to perform extensive therapeutic drug monitoring (AUC) on particular occasions next to the routine follow up of trough/C2 levels after transplantation. The timing of AUC monitoring should be determined by: time after transplantation (for example 3 months, 6 months, 1 year, etc.), relevant and long-term alterations in: comedication (steroids, calcium channel blockers, antifungals), diet, body composition, and changes in disease/organ function. In addition, phenomena related to CNI under or overexposure such as allograft rejection and chronic nephrotoxicity should urge the clinician to reevaluate CNI therapy. The long-term benefit of initial dosing based upon genotype is still not clear. However, genetic variation is not only important for dose requirements in relation to exposure, but also plays a role in drug toxicity and drug-drug interactions independent of exposure. We therefore advocate the routine pharmacogenetic assessment of an allograft recipient (and donor if possible) participating in clinical trials that collect and present pharmacokinetic data in relation to outcome. Further exploration of the complex correlation between different pharmacokinetic determinants and its relevance within a certain subject will help the creation of “virtual populations”. This so-called in vitro-in vivo extrapolation (IVIVE) will allow us to better predict pharmacokinetic parameters and thus the adequate dosage in more “extreme” individuals versus the “average patient“. To achieve this, additional data are needed on the functional effect of the different genotype combinations within each compartment. Recently our group created an in vitro model of proximal tubular cell lines derived from kidney allografts with different variants of CYP3A5 and ABCB1 with the objective to study the effect of different genotype combinations on CNI metabolism in the kidney (unpublished data). Barter et al. performed simulations in a model based on hepatic microsomal protein expression in a genetic heterogeneous population. They demonstrated that for a compound that is more extensively metabolized by CYP3A5 than CYP3A4, such as

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tacrolimus, failure to consider the incorporation of the relationship between CYP3A4 and CYP3A5 resulted in a 32% lower estimate of oral clearance in certain subpopulations (Barter et al., 2010). Gertz et al. performed bioavailability predictions for 12 CYP3A substrates within a physiologically based pharmacokinetic (PBPK) model using in vitro permeability and clearance data. The prediction success was assessed in comparison with the Q(Gut) model and in vivo observations from meta-analyses. The predicted oral clearance values of the drugs (including tacrolimus) were overall within 3-fold of the observed (Gertz et al., 2011). Phapale et al. made use a of metabolic phenotyping approach in which they performed a LC-MS based metabolic profiling of the urine in a group of healthy volunteers before and during tacrolimus therapy (Phapale et al., 2010). They identified a set of metabolites that demonstrated a relation with tacrolimus PK and constructed a hypothetical network on their role in tacrolimus disposition. Although the majority of these metabolites were never reported to be associated with tacrolimus PK, the predicted AUC of this “pharmacometabolomic approach” corresponded well with the actual measured tacrolimus AUC (r = 0.917), urging the community to further validate this model within other and larger populations and investigate the possible relationship of these metabolites with tacrolimus metabolism and transport. Through the combination of different covariates such as CYP3A4 activity, CYP3A5 genotype and hematocrit we were able to explain already 60–72% of variability in tacrolimus dose requirements in a cross-sectional study in 59 renal transplant patients (de Jonge et al., 2012). However, important gaps in our knowledge still need to be filled. This calls for a concerted effort by clinicians, basic scientists and pharmacologist to further explore the pharmacokinetic capacities of currently known enzymes and transporters within the different compartments and according to the common genetic variation in their functional expression. Furthermore, additional possible determinants of CNI exposure have to be identified. With these data integrative multicompartment predictive models can be constructed and tested for the different populations. Until then the true concept of tailored treatment is still far from clinical practice. Support and financial disclosure declaration: Noël Knops is supported by a clinical research grant “KOF mandaat” provided by the University Hospital Leuven. References Amirimani, B., Ning, B., Deitz, A.C., Weber, B.L., Kadlubar, F.F., Rebbeck, T.R., 2003. Increased transcriptional activity of the CYP3A4*1B promoter variant. Environ. Mol. Mutagen. 42, 299–305. Amundsen, R., Asberg, A., Ohm, I.K., Christensen, H., 2012. Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro. Drug Metab. Dispos. 40, 655–661. Anglicheau, D., Thervet, E., Etienne, I., Hurault De Ligny, B., Le Meur, Y., Touchard, G., Buchler, M., Laurent-Puig, P., Tregouet, D., Beaune, P., Daly, A., Legendre, C., Marquet, P., 2004. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin. Pharmacol. Ther. 75, 422–433. Anglicheau, D., Verstuyft, C., Laurent-Puig, P., Becquemont, L., Schlageter, M.H., Cassinat, B., Beaune, P., Legendre, C., Thervet, E., 2003. Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. J. Am. Soc. Nephrol. 14, 1889–1896. Bader, A., Hansen, T., Kirchner, G., Allmeling, C., Haverich, A., Borlak, J.T., 2000. Primary porcine enterocyte and hepatocyte cultures to study drug oxidation reactions. Br. J. Pharmacol. 129, 331–342. Bai, S., Liu, J., Lu, S.K., Brunner, L.J., 2001. In vivo induction of hepatic p-glycoprotein by cyclosporine in the rat. Res. Commun. Mol. Pathol. Pharmacol. 109, 103–114. Ball, S.E., Scatina, J., Kao, J., Ferron, G.M., Fruncillo, R., Mayer, P., Weinryb, I., Guida, M., Hopkins, P.J., Warner, N., Hall, J., 1999. Population distribution and effects on drug metabolism of a genetic variant in the 5‘promoter region of CYP3A4. Clin. Pharmacol. Ther. 66, 288–294. Barraclough, K.A., Isbel, N.M., Johnson, D.W., Campbell, S.B., Staatz, C.E., 2011. Onceversus twice-daily tacrolimus: are the formulations truly equivalent? Drugs 71, 1561–1577.

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