The Effects of CKD on Cytochrome P450–Mediated Drug Metabolism

The Effects of CKD on Cytochrome P450–Mediated Drug Metabolism Matthew A. Ladda and Kerry B. Goralski CKD affects a significant proportion of the world’s population, and the prevalence of CKD is increasing. Standard practice currently is to adjust the dose of renally eliminated medications as kidney function declines in effort to prevent adverse drug reactions. It is increasingly becoming recognized that CKD also impacts nonrenal clearance mechanisms such as hepatic and intestinal cytochrome P450 (CYP) enzymes and drug transport proteins, the latter of which is beyond the scope of this review. CYPs are responsible for the metabolism of many clinically used drugs. Genetics, patient factors (eg, age and disease) and drug interactions are well known to affect CYP metabolism resulting in variable pharmacokinetics and responses to medications. There now exists an abundance of evidence demonstrating that CKD can impact the activity of many CYP isoforms either through direct inhibition by circulating uremic toxins and/or by reducing CYP gene expression. Evidence suggests that reductions in CYP metabolism in ESRD are reversed by kidney transplantation and temporarily restored via hemodialysis. This review summarizes the current understanding of the effects that CKD can have on CYP metabolism and also discusses the impact that CYP metabolism phenotypes can have on the development of kidney injury. Q 2016 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Renal insufficiency chronic, Cytochrome P-450 enzyme system, Pharmacogenetics, Pharmacokinetics, Drug metabolism

INTRODUCTION CKD is defined as a progressive decline in kidney function for a period of at least 3 months and is classified by cause, glomerular filtration rate (GFR) category, and albuminuria category.1 With an estimated worldwide prevalence of 8% to 16%, CKD is a major cause of morbidity and mortality and a significant contributor to the burden of chronic disease.2 In many parts of the world, the burden of CKD has increased over the past 20 years.3 Furthermore, the number of people with CKD is projected to remain on an upward trajectory as the prevalence of diabetes, hypertension, and obesity increases, all of which are leading risk factors for CKD. The management of patients with CKD can be complex due to the prevalence of comorbid conditions such as hypertension and diabetes, as well as the drug-dosing modifications that must be done corresponding to the patient’s severity of disease. As an example of this complexity, dialysis patients have been found to have a median daily pill burden of 19, among the highest for any chronic disease state.4 Estimated GFR is typically used to classify the severity of a CKD case, and using the estimated GFR to adjust the dosage of drugs that are primarily renally eliminated is currently standard practice in the management of patients with CKD to prevent the accumulation of drug in the body and subsequent adverse effects.5 Despite the existence of numerous guidelines regarding the dose adjustment of renally eliminated medications in patients with CKD, impaired kidney function remains to be associated with an increased risk of adverse drug events.6 However, 1 factor that is often not taken into consideration is that kidney disease impacts nonrenal clearances in addition to kidney clearances. Dose adjustments to accommodate for these decreases in nonrenal clearances are not common practice. It is possible that this lack of consideration given to the impact of declining kidney function on nonrenal clearances may account for some of the increased occurrence of adverse effects seen in CKD patients.

The impact of nonrenal clearances such as reduced cytochrome P450 (CYP) enzyme and drug transporter function on the pharmacokinetics of drugs administered to CKD patients is increasingly being demonstrated in the literature.7 The United States Food and Drug Administration has recently published a draft guidance document for industry regarding pharmacokinetic studies in patients with impaired kidney function.8 Contained within this document is the recommendation that pharmacokinetic studies in kidney impairment models be conducted for medications intended for chronic use, including those of which are not eliminated renally, acknowledging the fact that nonrenal clearance mechanisms can be altered in CKD. Furthermore, with an increasing awareness of the influence of genetics on pharmacotherapy, more studies are now considering how genetic polymorphisms affecting CYP function contribute to altered drug pharmacokinetics in CKD or the development of kidney disease itself. The aim of this article was to provide an update on the impact of CKD on the function of the major drugmetabolizing CYPs and insight into the impact of CYP pharmacogenetics on drug disposition in CKD. Overview of Cytochrome P450 Enzymes in Drug Metabolism and Pharmacokinetics The pharmacokinetic processes of drug absorption, distribution, metabolism, and excretion are highly influenced From the College of Pharmacy, Faculty of Health Professions, Dalhousie University, Halifax, NS, Canada; and Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Kerry B. Goralski, PhD, College of Pharmacy, Dalhousie University, 5968 College Street, PO Box 15000, Halifax, NS, Canada B3H 4R2. E-mail: [email protected] Ó 2016 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2015.10.002

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by the coordinated action of many different drug metaof the systemic half-life (t1/2), and reduction in oral clearbolism enzymes including CYPs and drug transporters ance (CL/F). These changes are consistent with a reduction in the intestines, liver, and kidney (Fig 1). With regard to in CYP metabolism leading to increased oral bioavailthe involvement of CYPs in these pharmacokinetic proability and/or reduced systemic elimination and are not cesses, the 6 isozymes CYP1A2, CYP2C9, CYP2C19, necessarily trivial. For example, the intravenously adminCYP2D6, CYP3A4, and CYP3A5 collectively are responistered CYP3A4 substrate and nonrenally cleared drug sible for the metabolism of 90% of drugs.9 Individual midazolam had a 6-fold higher systemic exposure when drugs can be metabolized by either a single CYP enzyme given to hemodialysis patients immediately before a dialor multiple CYP enzymes and are typically converted to ysis session compared to healthy controls.11 Thus, for drugs that have a small range of therapeutic concentramore polar inactive metabolites that are more readily elimtions, the impact CKD can have on CYP metabolism is inated in the bile or urine than the parent compound. In likely clinically significant. Reflecting this, for a number some cases, active metabolites of prodrugs can also be proof the CYP-metabolized drugs listed in Table 1 (highduced as in the case of the CYP2D6-mediated conversion lighted with asterisks), dose adjustments, cautions, or of codeine to morphine. The CYP enzymes are most abunavoidance of use are recommended with advanced stages dant in the liver, and the liver is generally appreciated to be of CKD. the most important organ for systemic drug metabolism. In addition, certain CYP isoforms are found in other Experimental Evidence Supporting Reduced CYP organs where they mediate local metabolism and may Function in CKD contribute to tissue-specific effects of drugs.10 For example, in the human intestine, CYP3A4 predominates With mounting evidence supporting enhanced oral and plays an important role bioavailability and/or in first pass metabolism and decreased systemic eliminaCLINICAL SUMMARY the oral bioavailability of tion of many different CYPdrugs, whereas in the kidmetabolized drugs in CKD,  There are numerous examples of predominantly ney, the expression of research efforts have attempcytochrome P450 (CYP)–metabolized medications that CYP2B6 and CYP3A5 has ted to experimentally model display altered pharmacokinetics in CKD. been confirmed.10 this phenomenon to uncover  Pharmacokinetic alterations occur in CKD because of a Acute and chronic the mechanisms underlying reduction in hepatic and/or intestinal CYP metabolism diseases, drug–drug and these changes. Several aniand most often manifest as an increased oral drug–food interactions, and mal studies carried out by bioavailability, greater systemic exposure, and prolonged other patient-specific factors Pichette and colleagues over half-life of the affected drug. including genetics, age, the past 2 decades have  In end-stage CKD, the pharmacokinetic alterations can be gender, and obesity can been instrumental in this reversed by kidney transplantation and temporarily lead to variability of CYP regard. This work most often restored via hemodialysis. metabolism within a populaused the 2-stage 5/ tion or within the same indi6-nephrectomy rat model of  Health-care providers should recognize that altered CYP vidual at different times, CKD. In these studies, CKD metabolism is a potential factor leading to variability of which may sometimes rats showed significant drug responses and adverse drug events in patients with CKD and that dosing adjustments may be required in necessitate drug dosing or reductions in CYP2C11 and some situations. drug therapy alterations. CYP3A1/2 enzyme activity With this known fact, it is and protein levels that were not surprising that CKD can later linked to a reduction in also significantly impact CYP metabolism. messenger RNA (mRNA) of the respective genes.12,13 CYP1A2, CYP2D1/2, and CYP2E1 were not affected Observations of Pharmacokinetic Alterations of CYPindicating that CKD affects some but not all hepatic CYPs in rats. Recent research has validated the effect of Metabolized Drugs in Humans with CKD CKD on hepatic CYP3A2 and CYP2C11 enzyme Over the past 301 years, there have been many reports of expression and activity in rats while showing that degree altered pharmacokinetics of drugs that are moderately or of enzyme expression had an inverse exponential extensively metabolized by CYPs in patients with CKD. correlation to kidney function.14 These results are interTable 1 summarizes a selection of affected orally or esting in that they suggest that significant changes in intravenously administered drugs. Many affected drugs CYP metabolism could occur even in those with mild kidare metabolized by CYP3A4, which is understandable ney impairment. given that the CYP3A family metabolizes approximately 50% of clinically used drugs. Alterations in the pharmacoThe Molecular Mediators and Mechanisms Leading to kinetics of CYP1A2, CYP2B6, CYP2C9, and CYP2D6Reductions in Hepatic CYP Metabolism in CKD metabolized drugs have also been reported in CKD and In CKD patients there is retention of a variety of solutes could lead to excessive exposure of many different medicaknown as uremic retention solutes that are otherwise tions that are metabolized by these enzymes (Table 2). excreted in healthy patients.15 Uremic retention solutes Most frequently reported are an increase in area under can be classified as free water-soluble low molecular the curve, that is, a measure of systemic drug exposure, weight molecules (eg, reactive carbonyl compounds), the maximal plasma concentration (Cmax), a prolongation

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Figure 1. The role of cytochromes P450 (CYPs) and drug transport proteins in absorption, metabolism, and excretion of drugs. Various solute carrier (SLC) transporters mediate the uptake of drugs from the intestine into the intestinal enterocytes contributing to drug absorption after oral dosing. The sequential action of SLC-mediated drug uptake across basolateral membranes in the liver or kidney followed by drug efflux across the canalicular membrane (liver) or brush border membrane (kidney) via other SLC transporters or adenosine triphosphate-binding cassette transporters (ABC) contributes to biliary or kidney drug excretion, respectively. By influencing cellular drug uptake, SLC transporters also facilitate intracellular CYP metabolism and phase II conjugation reactions (not shown), whereas the ABC transporters can also facilitate the biliary and kidney excretion of drug metabolites. The transporters shown in red mediate cellular drug uptake, and those shown in green mediate cellular drug efflux. Black hexagons and orange circles represent the parent drug and metabolites, respectively.

protein-bound molecules (eg, indoxyl sulfate and hippuric acid), and middle molecular weight molecules (eg, parathyroid hormone [PTH] and cytokines). Uremic retention solutes that negatively impact biological function when they accumulate are called uremic toxins. There are several studies that support the involvement of uremic toxins in hepatic CYP regulation in CKD. When primary rat hepatocytes from healthy rats were incubated for 24 hours with 10% serum from CKD rats, a comparable reduction in CYP2C11 and CYP3A1/2 but not CYP2D1/2 mRNA, protein, and activity were observed linking the changes in CYP function to uremic toxins present in the circulation.16 When a similar experiment was performed using 10% serum from humans with CKD, the impact on CYPs was more widespread as the decreased expression of CYP3A2 and CYP2C11 as well as CYP1A2, CYP2C6, CYP2D1/2, and CYP4A1/3 were observed.17 It was also found that serum from ESRD patients obtained during the immediate predialysis but not the immediate postdialysis periods reduced rat hepatic CYPs implicating that the uremic toxins responsible for CYP regulation are at least temporarily reduced by hemodialysis.17,18 In comparison to intermittent hemodialysis, patient serum obtained 2 months after successful kidney transplantation did not affect the rat hepatocyte CYP expression and function

supporting that a restoration of kidney function restores normal hepatic CYP metabolism.17 In earlier clinical studies, 14C-erythromycin breath test (EBRT) values (an indicator of hepatic CYP3A4 activity) were 28% lower in patients with ESRD compared to healthy age-matched controls19 and increased by 27% in ESRD patients in the immediate post- vs pre-hemodialysis periods.20 These in vivo findings suggested that CYP3A4 activity is reduced in ESRD and transiently improved after uremic toxins are removed from the blood by hemodialysis. However, it was later discovered that changes in erythromycin cellular accumulation arising from induction or inhibition of the organic anion-transporting polypeptide and p-glycoprotein drug transporters influence EBRT values.21 Thus, the demonstrated influence of CKD on hepatic and intestinal drug transporters must also be considered as a possible explanation for the EBRT results.22 More recent studies have used midazolam to selectively probe CYP3A4 activity in ESRD patients undergoing hemodialysis and have produced contradictory results.11,22 Thomson and colleagues reported that systemic midazolam exposure was significantly increased in the hemodialysis group compared to healthy controls, whereas Nolin and colleagues did not find a significant difference in midazolam pharmacokinetics between groups. The

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Table 1. Representative Drugs that are Moderately or Extensively Metabolized by Cytochrome P450 (CYP) that Show Reduced Nonrenal Clearance and/or Oral Bioavailability in CKD Drugreference Aliskiren*

,44

1 hepatic CYP metabolism pathway CYP3A4

Alfuzosin*,45

CYP3A4

Bupropion46

CYP2B6 (active metabolites)

Carvedilol47 Ciprofloxacin*,48

CYP2C9, 2D6, 3A4, 2C19, 1A1, and 2E1 CYP1A (40%-50%)

Cyclophosphamide*,49 Duloxetine*,50

CYP2B6, 2C9, and 3A4 (inactive and active metabolites) CYP1A and CYP2D6

Erythromycin†,51

CYP3A4

Solifenacin*,52

CYP3A4 (active/inactive metabolites)

Tadalafil*,53 Telithromycin*,54 Warfarin*,55

CYP3A4 CYP3A4 (50%) CYP2C9

PK changes after oral dosing in CKD [ AUC and Cmax that did not correlate with CLCR \ AUC and Cmax \ t1/2 (with severe CKD) \ AUC, Cmax, and t1/2 Z CL/F \ AUC, Cmax, and 5 t1/2 \ AUC, 75% Z in CLR and 50% Z in CLNR \ AUC, Z CLtotal (intravenous dosing) \ AUC and Cmax, \oral F suggested \ CLH and Z oral F no correlation with uremic toxins CMPF and indoxyl sulfate \ AUC and t1/2, Z CL/F (trend) CL/F correlates with CLCR \ AUC and t1/2 and Z CL/F \ AUC and Cmax ss Reduced dosing requirements in moderate and severe CKD

Abbreviations: AUC, area under the curve; CL/F, oral clearance; CLCR, creatinine clearance; CMPF, 3-carboxy-4-methyl-5-propyl-2-furanproprionic acid; PK, pharmacokinetics. *Dose adjustments, cautions, or use avoidance are recommended for advanced stages of CKD. †Erythromycin is also a substrate for various drug transporters; therefore, changes in erythromycin pharmacokinetics in CKD cannot be solely attributed to CYP3A4 activity.

discrepancy may relate to the routes of midazolam administration: oral in the study by Nolin and colleagues and intravenous in the study by Thomson and colleagues. However, if hemodialysis temporarily restores CYP function, then the differential timing of the midazolam pharmacokinetic studies relative to the patients’ last hemodialysis session could explain the contradictory results. The study by Nolin and colleagues was conducted 1 day after hemodialysis, where uremic toxins that influence CYP3A4 may still be depleted resulting in normalized CYP3A4 function. The study by Thomson and colleagues was conducted approximately 58 hours after the last hemodialysis session, a point at which the uremic toxins and their inhibitory effects of CYP3A4 function would be expected to at a maximum. When fractioned serum from human ESRD subjects was applied to rat hepatocytes, it was identified that the 0-30 kDa fraction that would contain unbound small and most middle molecular weight uremic toxins decreased CYP3A2 protein to a similar degree as unfractionated serum.15,17 In addition, mRNA levels of CYP3A2 were specifically reduced by serum factors with a molecular weight between 10-15 kDa. PTH was postulated to be a mediator as it has a molecular weight within this range, and the inhibitory effect of uremic serum on rat hepatocyte CYP3A2 strongly correlated with PTH concentration. Furthermore, in humans, the mean uremic concentration of PTH is approximately 11 times that in healthy controls.15 In a subsequent study, depletion of PTH with antibodies prevented the effect of uremic serum on hepatic CYPs,

whereas adding back recombinant PTH restored the effect supporting a role for PTH.23 It has also been noted that concentrations of inflammatory cytokines such as interleukin-6, tumour necrosis factor (TNF) and interleukin-1b are increased in ESRD.15 These cytokines are well known to decrease hepatic CYPs, so, they could be contributing to the observed effects in CKD.24 Interestingly, in a study by Nolin and colleagues, the improvements in CYP3A4 activity from predialysis to postdialysis could not be correlated with changes in PTH or TNF concentrations.20 This result may have been due to the relatively small sample size of the study, but, it also could imply that uremic toxins other than PTH and TNF contribute to the reductions in CYPmediated metabolism observed in CKD. There is evidence that uremic mediators directly inhibit CYP enzymes. One study has shown that the combination of free or protein-bound small molecular weight uremic toxins benzyl alcohol, p-cresol, indoxyl sulfate, hippuric acid produced greater than 50% acute reductions in the activities of CYP1A2, CYP2C9, CYP2E1, CYP3A4 in vitro at concentrations similar to those found in CKD patients.25 Supporting a role for small molecular weight uremic toxins, Volpe and colleagues showed that 3-carboxy-4methyl-5-propyl-2-furanpropanoic acid, hippuric acid, and p-cresol inhibited CYP3A4 metabolism of testosterone in human liver microsomes at concentrations that are within the range observed in chronic kidney failure.26 However, the enzyme activity of CYP3A4 and CYP2B6, the latter of which is responsible for the metabolism of the antidepressant, and smoking-cessation aid bupropion,

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Table 2. Examples of Clinically Used Drugs that are Substrates of Various Cytochrome P450 (CYP) Enzymes CYP

Select Substrates

CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP3A4/A5

Caffeine, cyclobenzaprine, duloxetine, fluvoxamine, mirtazapine, olanzapine, propranolol, theophylline Bupropion, cyclophosphamide, efavirenz, ifosfamide, methadone, propofol, selegiline Celecoxib, glipizide, glyburide, losartan, meloxicam, phenytoin, warfarin Citalopram, clopidogrel, diazepam, pantoprazole, progesterone Codeine, fluoxetine, methamphetamine, metoprolol, mirtazapine, propranolol, risperidone, tamoxifen, venlafaxine Amiodarone, amlodipine, atorvastatin, budesonide, carbamazepine, citalopram, clonazepam, colchicine, cyclosporine, diazepam, diltiazem, domperidone, doxorubicin, erythromycin, felodipine, fentanyl, haloperidol, lapatinib, mirtazapine, nifedipine, ondansetron, oxycodone, paclitaxel, quinine, tacrolimus, verapamil

was not different when the human liver microsomes were treated with predialysis vs postdialysis serum from ESRD patients. This could be due to small sample size of the study but may also imply that uremic toxins influence CYP gene expression. Although some studies have found that uremic toxins directly inhibit CYP enzymes, others have found reductions in gene expression to be responsible for at least some of the decrease in CYP activity observed in CKD (Fig. 2A). Velenosi and colleagues demonstrated the reduction of CYP2C11 and CYP3A2 in the 5/6-nephrectomy rat CKD model resulted from decreased binding of the nuclear transcription factors pregnane X receptor (PXR)/retinoid X receptor heterodimer, hepatocyte nuclear factor 4, and RNA polymerase II to rat CYP2C11 and CYP3A2 promoter regions.27 These changes in nuclear transcription factor binding were accompanied by a transcriptionally silent state mitigated by the reduction in histone-4 and histone-3 acetylation in the CYP3A11 and CYP2C11 promoters, respectively.27 This latter discovery is particularly interesting as it provides a mechanism for a chronic alteration in CYP expression and function while also lending support to the idea of a role for epigenetic mechanisms (a collection of processes that switch genes on or off in response to environmental factors) in CKD and its comorbid conditions (Fig. 2B). Michaud and colleagues demonstrated that inhibition of nuclear factor kappa B (NF-kB) could almost completely abrogate the effect of human ESRD serum on rat hepatocyte CYPs.18 In response to inflammatory mediators, NF-kB depresses human CYP3A4 transcription by interfering with the association of PXR/retinoid X receptor within the CYP3A4 promoter.28 Thus, the NF-kB-mediated effect demonstrated by Michaud links to the PXRmediated effect shown by Velenosi providing a probable mechanism for uremic mediators such as PTH and inflammatory cytokines, which activate NF-kB signaling to reduce hepatic CYP expression and function. In summary, most experimental evidence supports that the decrease in CYP activity seen in patients with CKD involves uremic toxins, which alter signal transduction mechanisms leading to transcriptional and/or translational modifications. Although there are some contradictory findings, the direct inhibition of CYPs by uremic toxins has also been observed. Furthermore, a newly discovered role for epigenetic regulation also exists. Thus, it is likely that there are multiple mechanisms underlying the alterations in CYP metabolism in CKD.

CYP P450 Polymorphisms and Drug Metabolism in CKD Variations in the metabolic capacity between individuals can arise due to genetic polymorphisms of CYP enzymes that exist within a population. A genetic polymorphism refers to multiple forms of the same gene that are typically caused by a single nucleotide change in the coding or regulatory regions of a gene. When genetic polymorphisms produce amino acid substitutions, alterations in the transcription, expression, and/or function of a specific CYP can arise. This can lead to a poor metabolizer phenotype, especially when individuals are homozygous for the mutant CYP. For example, CYP2C9 poor metabolizers metabolize the drug warfarin more slowly than individuals who possess 2 copies of the normal CYP2C9 gene and thus may require lower doses of warfarin to achieve the desired therapeutic effect. In some cases, genetic alterations result in higher than normal CYP metabolism as in the case of CYP2D6, where a gene duplication event has led some individuals to contain more than 2 copies of the normally functioning CYP2D6 gene. This leads to an ultrarapid metabolic phenotype and can influence drug responses and toxicity. For example, due to rapid metabolism of codeine to the active metabolite morphine, CYP2D6 ultrarapid metabolizers have an increased risk for experiencing adverse drug effects from codeine. Reflecting the recent advances in pharmacogenetics, clinical practice guidelines have been developed for implementation of CYP2C9 and CYP2D6 pharmacogenetics in warfarin and codeine dosing respectively in the United States and Canada.29,30 With respect to kidney function, there are also some emerging examples from the literature suggesting that excessive exposure to nephrotoxic drugs due to CYP polymorphisms may contribute to acute or chronic kidney injury. Furthermore, research into the benefits of genotypespecific dosing for certain drugs has already begun. Tacrolimus, a calcineurin inhibitor used to prevent rejection after solid organ transplant, is metabolized by CYP3A4/5. It has been established that CYP3A5 expressors require higher maintenance doses than CYP3A5 nonexpressors as a result of higher oral bioavailability and reduced systemic elimination.31 Pharmacokinetic models also demonstrate that due to the absence of kidney CYP3A5, non-expressors will accumulate higher amounts of tacrolimus in the kidney epithelium,32 which could serve as a mechanism for increased risked of tacrolimusinduced nephrotoxicity. However, there are conflicting

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Figure 2. (A) Representative mechanisms of cytochromes P450 (CYP) regulation in CKD. In individuals with normal kidney function, various nuclear transcription factors (TFs) are synthesized, activated, and bind to promoter regions of the CYP genes leading to transcription of CYP messenger RNA (mRNA), which is then translated into the functional CYP enzymes and normal drug metabolism. As CKD develops, the accumulation of uremic toxins in blood occurs. These includes macromolecules such as parathyroid hormone and inflammatory cytokines, which bind to cell surface receptors to activate intracellular signaling pathways that repress CYP gene transcription leading to reduced CYP mRNA and ultimately functional CYP enzymes. A

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clinical data regarding the role of CYP3A5 polymorphisms in the development of tacrolimus-related nephrotoxicity.33,34 Despite this controversy, 1 recent study demonstrated that CYP3A5 genotype–specific dosing was beneficial with respect to decreasing acute rejection and hepatic and kidney toxicity.35 As suggested by a recent study, proton pump inhibitors (PPIs) are an underappreciated cause of acute kidney injury.36 The PPIs are all primarily metabolized by CYP2C19, and genetic polymorphisms leading to CYP2C19 poor-metabolizer phenotypes of PPIs have been characterized. There is at least 1 documented report of acute kidney injury in a CYP2C19 poor metabolizer receiving lansoprazole therapy.37 It is possible that certain cases of acute kidney injury secondary to PPI use are due to a poor metabolizer phenotype, although trials are needed to confirm an association. In cases where drug metabolites are nephrotoxic, genetic polymorphisms leading to reduced CYP function may actually be protective. For example, the conversion of ifosfamide to its nephrotoxic metabolite chloracetaldehyde in human liver and kidney microsomes is significantly reduced in CYP3A5 non-expressors.38 The theoretical possibility that CYP3A5 non-expressor variants could be kidney-protective in the case of ifosfamide remains to be demonstrated in humans. Implications for Currently Used Drug Therapies Because CYP enzymes metabolize 90% of drugs, the alterations found in CKD could impact a wide variety of drug therapies. Perhaps, of particular interest are drugs with a narrow therapeutic index and nephrotoxic drugs. Narrow therapeutic index drugs that are significantly metabolized by CYP enzymes theoretically should be dosed conservatively until patient response is known to avoid adverse effects, although further research is required before any broad recommendations can be made. In regard to nephrotoxic drugs, it is already known that patients with preexisting kidney impairment are at greater risk of nephrotoxicity.39 A few examples of CYP-metabolized nephrotoxic medications include tacrolimus and ifosfamide as mentioned previously, and also nonsteroidal anti-inflammatory drugs such as celecoxib. Although it is generally recommended to avoid nephrotoxic medications in patients with CKD, there are times when no alternative therapies exist and the benefit of using the medication outweighs the risk. Because patients with CKD have a reduced ability to metabolize medications through CYP pathways, these nephrotoxic medications may achieve

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greater systemic concentrations, resulting in kidney injury. This is 1 potential mechanism explaining the greater risk of nephrotoxicity in patients with baseline kidney impairment, although further research is required to confirm this. Future Research Directions The effect of CKD on CYP metabolism and drug pharmacokinetics is ultimately influenced by multiple factors including the route of drug administration, the CYP isoform, the drug in question, the CYP location (eg, hepatic vs intestine), the type and stage of kidney disease as well as dialysis in ESRD.11,14,17,18,22,40 Furthermore, the pharmacokinetics of CYP-metabolized drugs may also be influenced by various drug transporters, which are also affected by CKD.41 As a result, it is currently difficult to predict how CKD will impact the pharmacokinetics of a particular drug based on data from another drug of the same class or another drug metabolized by the same CYP enzyme. Additional research into how these factors influence the pharmacokinetics of individual drugs is needed to enable the development of quantitative dosing predictions for primarily CYP-metabolized drugs in CKD. The impact of CKD on CYP-mediated metabolism when accounting for CYP polymorphisms is currently unknown. The results from a recent drug interaction study support that there could be links. In this study, CYP3A4 inhibition by erythromycin and mild to moderate kidney impairment interacted to produce additive effects on the systemic exposure to the oral anti-coagulant rivaroxiban.42 In a similar vein, it will be important to assess how CYP polymorphisms and CKD interact to affect drug pharmacokinetics. For instance, in the event that there are additive or synergistic effects on oral bioavailability and/or systemic exposure, what are the consequences for drug dosing, drug responses, and adverse drug effects? If the reduction in CYP-mediated metabolism in CKD is additive with the reduction in CYP-mediated metabolism due to polymorphisms, would it be possible to preemptively identify individuals at risk of nephrotoxicity and prevent further kidney injury? Unfortunately, these questions currently cannot be answered definitively and require further research. Although the overwhelming evidence supports that reductions in hepatic CYPs occur in CKD, there are some inconsistencies and unknowns with respect to the mechanisms and mediators in humans. In addition, species differences in CYPs and their regulation as well as potential differences in uremic toxins generated in the rat vs human require that mechanism of action studies be validated

second mechanism may involve direct inhibition of CYP metabolism by uremic toxins (colored triangles) that pass into the cell. By removing uremic toxins, hemodialysis appears to temporarily restore normal metabolism, whereas kidney transplantation has a more permanent effect. The (-) symbol denotes inhibition. Black hexagons and orange circles represent the parent drug and metabolites, respectively. (B) Epigenetic mechanisms of CYP regulation in CKD. In normal kidney function, chromatin associated-histone proteins are acetylated (AC) at specific residues causing the chromatin to exist open conformation allowing TFs to bind the CYP promoter regions on DNA, leading to normal transcription and translation into function CYP enzymes. In CKD, histone acetylation is reduced and could occur through increased histone deacetylase activity and/or decreased histone acetylase activity. This causes the chromatin to adopt a closed confirmation, which is in a transcriptionally silent state, thereby reducing the amount of function CYP enzymes produced. Black hexagons and orange circles represent the parent drug and metabolites, respectively. HNF4, hepatic nuclear factor 4; PXR/RXR, pregnane X receptor/retinoid X receptor heterodimer; RNA POL II, RNA polymerase II.

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using other models. For example, similar to the rat, effects of CKD on hepatic CYPs are observed in a mouse model of CKD.43 This finding is important as it opens the door to the utilization of transgenic mice with humanized CYPs (eg, CYP3A4 and 2D6) to elucidate a better understanding of the interactions between CKD on hepatic CYP metabolism and its relevance to humans. According to recent published data, at least 88 uremic retention solutes have been identified.15 Only relatively few of these have been studied with respect to their effects on CYP metabolism, and when they have been studied, they have typically been examined in isolation.25 There is a clear need for future research to investigate uremic toxins more broadly including how combinations of uremic toxins may act to influence CYP function. Potential applications of this knowledge could include the development of improved hemodialysis methods that further reduce the uremic burden, leading to greater stability in CYP metabolism in individuals with ESRD. CONCLUSION In conclusion, there is a plethora of evidence that uremic toxins reduce CYP-mediated metabolism through direct inhibition or by transcriptional downregulation. Many CYP isoforms have been found to have their activity reduced in CKD, and as a result, the metabolism of many medications used to treat CKD patients may be affected. To achieve optimal patient outcomes and prevent adverse drug effects, it is important for the clinician to consider the impact that alterations in CYP-mediated metabolism may have on the drug therapy of CKD patients. REFERENCES 1. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3(1):1-150. 2. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013;382(9888):260-272. 3. Jha V, Wang AY, Wang H. The impact of CKD identification in large countries: the burden of illness. Nephrol Dial Transplant. 2012;27(Suppl 3):iii32-iii38. 4. Chiu YW, Teitelbaum I, Misra M, de Leon EM, Adzize T, Mehrotra R. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients. Clin J Am Soc Nephrol. 2009;4(6):1089-1096. 5. Matzke GR, Aronoff GR, Atkinson AJ Jr, et al. Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80(11):1122-1137. 6. Chen YC, Fan JS, Chen MH, et al. Risk factors associated with adverse drug events among older adults in emergency department. Eur J Intern Med. 2014;25(1):49-55. 7. Momper JD, Venkataramanan R, Nolin TD. Nonrenal drug clearance in CKD: searching for the path less traveled. Adv Chronic Kidney Dis. 2010;17(5):384-391. 8. Guidance for industry, Pharmacokinetics in Patients With Impaired Renal Function—Study Design, Data Analysis, and Impact on Dosing and Labeling. 2010 [cited 2015 September 3rd]; Available at: http:// www.fda.gov/downloads/Drugs/.../Guidances/UCM204959.pdf 9. Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007;76(3):391-396.

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