Does P-glycoprotein play a role in anticancer drug pharmacokinetics?

P-glycoprotein and pharmacokinetics

Does P-glycoprotein play a role in anticancer drug pharmacokinetics? Alex Sparreboom, Kees Nooter Department of Medical Oncology, Rotterdam Cancer Institute and University Hospital Rotterdam, Rotterdam,The Netherlands

Abstract The multidrug-resistance P-glycoprotein is a drug efflux transport protein abundantly present in various types of human cancer.The protein is encoded by the MDR1 gene and its function is sensitive to modulation by competitive inhibition. Clinical studies have indicated that inhibitors of P-glycoprotein function dramatically decrease the systemic clearance of anticancer agents, necessitating dose reduction.This dose reduction not only complicated the interpretation of toxicity and response data, but also presented a serious obstacle in the development and rational use of P-glycoprotein inhibitors. It is now evident that the pharmacokinetic interference between anticancer drugs and P-glycoprotein inhibitors is due primarily to competition for drug metabolizing enzymes.A wealth of recent experimental data shows that many of the previously tested P-glycoprotein inhibitors, including verapamil, cyclosporin A, and valspodar (SDZ PSC 833), are substrates and/or potent inhibitors of cytochrome P450 3A4 (CYP3A4). Future development and clinical use of potent P-glycoprotein modulators lacking high affinity for CYP3A4 should decrease the impact of these important drug interactions and will eventually result in improved therapeutic specificity and efficacy. © 2000 Harcourt Publishers Ltd

INTRODUCTION reatment with cytotoxic drugs is one of the most important tools in the management of leukemias and disseminated or locally advanced inoperable cancers. However, intrinsic and/or acquired resistance of sub-populations of tumor cells to cytotoxic agents remains a major impediment to achieving complete and lasting remissions. In the last few decades, in vitro studies have elucidated a number of cellular mechanisms by which cells can become resistance to cytotoxic drugs.To date, the bestcharacterized form of drug resistance is caused by (over)expression of genes encoding membrane-localized, energydependant, outward drug pumps that facilitate the cellular efflux of several clinically important anticancer drugs. Thus far, three major classes of drug pumps, referred to as Pglycoprotein,1 multidrug resistance-associated protein (MRP1) and its homologues (MRP2 [cMOAT], MRP3, MRP4, MRP5, and MRP6),2–4 and breast cancer-resistance protein (BCRP; also referred to as MXR or ABCP1),5 have been characterized and might all play a role in clinical drug resistance.These proteins belong to the large superfamily of ATP-binding cassette transporters that are found in almost all prokaryotic and eukaryotic cells. P-glycoprotein was the first anticancer drug

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pump to be identified.The protein is encoded by the MDR1 gene, and genetic manipulation has elucidated its normal biological function as well as its role in multidrug resistance (MDR).The characteristic tissue distribution of P-glycoprotein expression is indicative of a role in detoxification and protection against xenobiotic substances. Indeed, genetic knockout of murine P-glycoprotein genes has shown decreased blood-brain barrier function,6 increased intestinal absorption7 and fetal drug exposure,8 and increased druginduced damage to testicular tubules, choroid plexus epithelium and oropharyngeal mucosa.9,10 In addition to their role as an integral component of host detoxification and protection mechanisms, evidence also suggests that P-glycoproteins may play a role in normal biliary transport, cholesterol trafficking11 and migration of dendritic cells and T-lymphocytes out of the skin.12 On the other hand, transgene-enforced overexpression of MDR1 confers an MDR phenotype which can be reversed by inhibitors of the P-glycoprotein drug pump. Studies performed over the last several years have shown that intrinsic and acquired expression of P-glycoprotein might play a significant role in clinical drug resistance in specific solid tumors and hematological malignancies. Consequently, clinical trials have been initiated worldwide in which P-glycoprotein inhibitors are given to cancer patients, along with anticancer drugs, with the intent of attenuating carrier-mediated drug resistance in vivo.13 In these clinical trials decreased systemic clearance of the anticancer drugs became a serious problem and necessitated dose reductions. Here we will review the mechanisms of potential drug–drug interactions and the results of comparative clinical pharmacokinetic studies of anticancer drugs given with and without MDR-modulating agents. CLINICAL RELEVANCE OF P-GLYCOPROTEIN MODULATION The P-glycoprotein-mediated MDR phenotype results from cross-resistance to a variety of structurally and functionally unrelated natural products used for cytotoxic anticancer therapy. These agents include the anthracyclines (doxorubicin, daunorubicin, and epirubicin), Vinca alkaloids (vinblastine and vincristine), epipodophyllotoxins (etoposide and teniposide) and taxanes (paclitaxel and docetaxel). In addition, P-glycoprotein transports many other clinically important classes of drugs, such as cardiac drugs (e.g. digoxin), antimicrobial (e.g. erythromycin, quinine, the HIV-1 protease inhibitors indinavir and saquinavir), anthelmintic (e.g. ivermectin), immuno-suppressive (e.g. tacrolimus), and steroids (e.g. dexamethasone and hydrocortisone). Apparently, P-glycoprotein has an extremely broad substrate specificity, which in fact is not well understood. Given this broad substrate specificity, it seems reasonable to expect that P-glycoprotein may have substantial impact on the efficacy of a large variety of drugs by modulating drug distribution and elimination. In this respect, the attempts to modulate P-glycoprotein-mediated MDR by specific, non-cytotoxic inhibitors might represent a learning curve for future applications. Since the first observation that verapamil could reverse MDR in vitro, a wide range of drugs, including quinidine, cyclosporin A, the R-risomer of verapamil (R-verapamil),  2000 Harcourt Publishers Ltd Drug Resistance Updates (2000) 3, 357–363 doi: 10.1054/drup.2000.0164, available online at http://www.idealibrary.com on

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Sparreboom and Nooter Table 1 Randomized comparative studies evaluating kinetic interactions between P-glycoprotein (P-gp) modulators and anticancer agents P-gp inhibitor

Total dose

Anticancer drug

Effect on drug

Ref.

17–70 mg/kg c.i.v. 42 mg/kg c.i.v. 42 mg/kg c.i.v.

etoposide doxorubicin doxorubicin

CL 40%↓ CL 55%↓ CL 37%↓

21 30 31

11.5 mg/kg c.i.v. 2–17 mg/kg c.i.v. 2.5–25 mg/kg bid p.o. 12.1 mg/kg c.i.v. 5 mg/kg qid × 3 p.o.

etoposide etoposide doxorubicin paclitaxel paclitaxel

CL 40%↓ CL 45%↓ CL 54%↓ no change no change

35 36 46 52 53

8640 mg/m2 c.i.v.

paclitaxel

CL 50%↓

57

200–300 mg bid × 5 p.o.

docetaxel

no change

17, 18

100–300 mg/m2 bid × 3 p.o.

docetaxel

no change

19

50–400 mg bid × 5 p.o.

doxorubicin

no change

20

cyclosporin A

Valspodar

biricodar R101933 LY335979 GF120918

Abbreviations: c.i.v., continuous i.v. infusion; CL, total plasma clearance.

nifedipine and progesterone, have been identified which can do so.These agents are thought to be competitive substrates for the drug pump and restore antitumor activity by increasing the intracellular concentration of a coadministered anticancer drug that otherwise would have been expelled from the cell. Initial attempts to improve therapeutic response in patients with P-glycoprotein-expressing cancers by standard chemotherapy and a P-glycoprotein inhibitor were primarily feasibility studies and failed to demonstrate any benefit of the experimental regimens.13 For solid tumors most of the phase II trials that followed were negative. However, for some hematological malignancies the clinical outcome of phase II trials was promising in the sense that unexpected responses were seen. In general, the phase II efficacy studies suffered from a number of serious problems hampering clear-cut interpretation. Among the shortcomings were: no documented P-glycoprotein expression in the tumor (and lack of tumor response on chemotherapy anyway), lack of consensus on standard P-glycoprotein assays, inappropriate dosing of P-glycoprotein inhibitor, the use of low-affinity inhibitors, and the application of dose reduction of standard chemotherapy regimens due to excessive toxicities. Despite the severe scrutiny of the design and performance of those early efficacy studies, the general idea still holds that especially in hematological malignancies the use of Pglycoprotein inhibitors finally will make a difference. Preliminary results of still ongoing phase II trials in leukemias and multiple myelomas seem to sustain this idea.14 358

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DRUG INTERACTIONS AND PHARMACOKINETICS Given the severe anticancer drug toxicities encountered in the MDR reversal trials, the need for proper evaluation of pharmacokinetic interactions between inhibitors and anticancer drugs has been recognized, although randomized comparisons have been performed in a few cases only (Table 1). Clinical application of anticancer drugs given in combination with first generation (verapamil, cyclosporin A) or second generation modulators (R-verapamil, valspodar) has proven highly problematic due to the occurrence of profound pharmacokinetic interactions. The vast majority of interactions are characterized by a dramatic decrease in systemic drug clearance, resulting in a need to reduce the dose of the anticancer drugs because of exacerbated toxicities (reviewed by Raderer and Scheithauer15).This change in the pharmacologic handling of the anticancer drugs has since been recognized as one of the principal problems by evaluating pharmacological, response and adverse effect data in P-glycoprotein-inhibition studies. Even in the absence of any effect of modulators on the concentration-toxicity response curve, these combinations of anticancer drugs with P-glycoprotein inhibitors are likely to narrow the therapeutic dosage range for anticancer drugs, because they will shift the dose-concentration curve.16 It has been proposed that the anticancer drug dose might be adjusted to achieve a target exposure measure (e.g.AUC) using adaptive-control schemes for individual treatment cycles, to enable differentiation

P-glycoprotein and pharmacokinetics between effects that can be attributed solely to the kinetic interaction and those attributable to P-glycoprotein inhibition. However, interpatient variability in the metabolism of drugs (e.g. through genetic polymorphism) would make this approach problematic. Furthermore, a requirement for dose reduction presents substantial problems for the use of P-glycoprotein inhibitors in up-front therapy. Fortunately, in recent years, third generation P-glycoprotein inhibitors with high potency have been reported which appear to lack significant kinetic interactions with anthracyclines or taxanes (Table 1: R101933-Ref. 17, 18; LY335979- Ref. 19; GF120918-Ref. 20). These novel inhibitors are clearly superior in the sense that they do not necessitate dose reduction and thus enable testing the full potential of MDR reversal by P-glycoprotein inhibitors. Several mechanisms have been postulated by which the early inhibitors could have altered the systemic kinetics of anticancer agents, including Pglycoprotein-mediated biliary and/or renal excretion, the presence of surfactants in pharmaceutical formulations, and enzyme-mediated interactions. P-glycoprotein mediated elimination process Initially, it was suggested that P-glycoprotein inhibitors may have profound effects on the disposition and behavior of anticancer drugs because impediment of P-glycoprotein expressed in biliary tract and renal tubules might inhibit active elimination processes.21 Clearly, drug elimination by these routes is important in the conceptualization of the effect of inhibitors on P-glycoprotein function, however, in practice, does not seem to play a major role. In man, cumulative bile and urine elimination of unchanged anticancer drugs may vary between 10 and 40% of the total administered dose, depending on the type of drug.22 So, inhibition of these elimination routes may potentially be of clinical importance. Recent comparative disposition studies performed in P-glycoprotein knockout mice have provided quantitative data on the role of P-glycoprotein in biliary and urinary excretion of unchanged anticancer drugs. The absence of P-glycoprotein did not have any substantial influence on the cumulative urinary excretion of doxorubicin,23 vinblastine24 or paclitaxel7 at any dose level tested. Similarly, biliary secretion of paclitaxel and vinblastine was also not influenced by the absence of P-glycoprotein.25, 7 However, for doxorubicin biliary secretion was indeed decreased from 13.3% of the dose to only 2.4% in the absence of P-glycoprotein.25 These findings suggest that the involvement of P-glycoprotein in the process of biliary secretion is strongly drug-dependent, and that, generally speaking, inhibition of that process is not very likely to contribute substantially to the increased plasma AUCs frequently observed in the P-glycoprotein inhibition studies. Role of formulation vehicles An intriguing observation from the pharmacokinetic studies performed in the P-glycoprotein-deficient mice, clearly designed to resemble the clinical situation, has been a general lack of effect of P-glycoprotein on the plasma pharmacokinetics of typical substrate drugs. For example, with vinblastine administered as a 96-h infusion, no significant difference in systemic drug clearance was observed between

P-glycoprotein knockout and wild-type mice at similar infusion rates.26 Similarly, doxorubicin clearance was only 1.2-fold slower in the knockout mice, caused by an almost imperceptible increase in the terminal disposition phase,23 whereas paclitaxel plasma concentrations following i.v. administration of the clinical formulation (Taxol) were also not significantly altered.27 Correspondingly, insignificant differences in the plasma levels of doxorubicin in mice were also observed in the presence of cyclosporin A formulated in olive oil.28 In contrast, treatment with cyclosporin A formulated in Cremophor EL, which is also used in clinical formulations, resulted in substantially increased exposure to doxorubicin in mice,29 similar to that observed in patients treated with i.v. cyclosporin A formulated in Cremophor EL.30,31 It has been demonstrated subsequently that this formulation vehicle can profoundly alter the plasma pharmacokinetics of doxorubicin and etoposide in animals and man.32–34 Since the clinical formulation of valspodar for i.v. administration also contains substantial amounts of Cremophor EL, it can be postulated that pharmacokinetic interactions with such inhibitors (e.g. with etoposide)35–37 is at least partially attributable to the use of this vehicle. Metabolic interferences It is particularly striking that both the anticancer drugs involved in the P-glycoprotein mediated MDR phenotype and the early P-glycoprotein inhibitors, are either confirmed or likely substrates for cytochrome P450 3A4 (CYP3A4). CYP3A4 is a subfamily of P450 that is quantitatively the most abundant in human liver, and can be induced or inhibited by a number of exogenous and endogenous compounds. This overlap in substrate specificity of CYP3A4 and P-glycoprotein appeared to be fortuitous rather than indicative of a more fundamental relationship.38 Verapamil,39 cyclosporin A,40 and valspodar41 are prototypical CYP3A4 substrates and subject to a host of enzyme-mediated drug interactions even when used at normal doses (reviewed by Dresser et al.42). It has been shown that the main enzyme catalyzing etoposide O-demethylation is also CYP3A4,43 and that cyclosporin A and valspodar, at concentrations achieved clinically could inhibit this metabolic pathway.41 The observed increases in the plasma concentrations of etoposide when combined with these agents may thus be the result of a combination of vehicle effects and inhibition of metabolism (hepatic and/or intestinal which will further enhance oral absorption with consequent further increase in plasma concentration). Similarly, Vinca alkaloids are also metabolized primarily by CYP3A4,44 making their elimination susceptible to inhibition by cyclosporin A and valspodar, a phenomenon that actually may have contributed to the earlier observation that vinblastine-induced toxicity is severely enhanced by cyclosporin A.45 The clinically observed increase, however, in doxorubicin exposure and reduced clearance in the presence of cyclosporin A30,31 or valspodar (given orally without Cremophor EL)46 is somewhat less easily explained, since doxorubicin itself is not metabolized by CYP3A4. It is conceivable, however, that these modulators can inhibit metabolic pathways while the parent drug (e.g. doxorubicin) is not being metabolized itself by this pathway.The somewhat more pronounced effects on the AUC of alcohol metabolites  2000 Harcourt Publishers Ltd Drug Resistance Updates (2000) 3, 357–363

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Sparreboom and Nooter Plasma concentration

Toxicity

Anthracyclines Epipodophyllotoxins Taxanes

Metabolism CYP3A4

P - glycoprotein inhibitors (first and second generation)

Fig. 1 Mechanism of decreased anticancer drug clearance and increased anticancer drug related toxicity by the use of first and second generation of P-glycoprotein inhibitors.

than on the AUC of the parent drug would support the notion that doxorubicinol may be a CYP3A4 substrate.47 Alternatively, recent work has shown that SKF-525A (a CYP3A4 inhibitor) significantly increased doxorubicin AUC by inhibition of doxorubicinol metabolism to deglycosylated aglycones, whereas dexamethasone (a CYP3A4 inducer) induced formation of the aglycones.48 It is thus likely that the inhibition of alternative metabolic routes by P-glycoprotein inhibitors results in shunting of parent drug to alcohol metabolites. Preclinical work has shown that cyclosporin A selectively inhibits the formation of the 3′-p-hydroxyl-metabolite of paclitaxel49 and causes a 50% reduction in paclitaxel clearance in mice.50 Clinically, cyclosporin A was also found to increase exposure to paclitaxel,13 although the effect appears to be less pronounced than in mice.This may relate to the fact that in human liver the major metabolite of paclitaxel appears to be 6α-hydroxy-paclitaxel, the formation of which is dependent on CYP2C8 rather than CYP3A4.51 Most likely the only moderately increased plasma AUC of paclitaxel in patients receiving valspodar (either i.v.52 or p.o.53) is also related to the lack of interference by this modulator in CYP2C8-mediated paclitaxel metabolism. The importance of a thorough understanding of CYP3A4mediated interactions with P-glycoprotein inhibitors as an essential step for their rational use has only recently been fully recognized (Fig. 1). Clearly, the development and use of P-glycoprotein modulators with minimal or absent CYP3A inhibitory effects should decrease the impact of drug interactions on the therapeutic use of such compounds. Wandel 360

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et al. has recently determined the apparent Ki values for CYP3A inhibition and the IC50 for P-glycoprotein inhibition for a series of modulators to allow comparison of the relative inhibitory potency of these agents on the proteins’ function.54 Their data indicated that, although many P-glycoprotein inhibitors are potent inhibitors of CYP3A, there is a varying degree of selectivity (i.e. the ratio of the IC50 for CYP3A to P-glycoprotein inhibition).Thus, even small structural modifications, such as cyclosporin A to valspodar, can profoundly after the selectivity of the drug (~40-fold difference in selectivity index). Using this selectivity index, it will be possible to screen compounds for the greatest inhibition of drug transport while minimizing loss of efficacy due to reduction in metabolic activation. The relevance of this principle is further underscored by the observation that some third generation P-glycoprotein modulators that exhibit nanomolar IC50s (e.g. GF120918,20 R101933,17,18 LY335979,19,55 and OC144–09356) and lack significant pharmacokinetic interaction with model substrate drugs, were also found to have very low affinity for CYP3A4, whereas those having high affinity for CYP3A4 also demonstrate significant pharmacokinetic interactions regardless of their potency as inhibitors of P-glycoprotein (e.g. biricodar, also known as VX-710).57 CONCLUSIONS AND PERSPECTIVES Over the last decade, clinical trials have been performed to determine the feasibility of adding P-glycoprotein inhibitors to standard chemotherapeutic regimens. The idealized

P-glycoprotein and pharmacokinetics putative clinical benefit is that their use will increase tumor response rates, without affecting the dose-toxicity curve (i.e. by increasing the therapeutic index). Given the overlap in specificity of enzymes responsible for metabolism of both anticancer drugs and P-glycoprotein inhibitors, it appears that increased toxicity can be anticipated based on a pharmacokinetic effect alone, thereby narrowing the therapeutic dosage range for anticancer drugs. Indeed, pharmacokinetic interactions have frequently necessitated major dose reductions for the anticancer drugs, thereby losing all the potential benefits in terms of antitumor activity as compared to normal dosages given without the addition of P-glycoprotein inhibitor. In recent years, a large body of evidence has been generated indicating that P-glycoprotein expressed in bile canaliculi or kidneys, previously postulated to be a major cause of drug interactions, actually plays only a very minor role in this process. Instead, the pharmacokinetic interference appears to be the result of competition for enzymes (mainly CYP3A4) involved in drug metabolism. In addition, the use of some polyoxyethylated surfactant vehicles for i.v. administered P-glycoprotein modulators may have a substantial impact on the interpretation of the anticancer drug’s pharmacokinetic behavior that has not been fully appreciated.58 A new generation of P-glycoprotein inhibitors that lacks the significant pharmacokinetic interaction with anticancer drugs is now available for efficacy testing in clinical trials for reversal of MDR. Eventually, the use of these agents will allow assessment of the contribution of P-glycoprotein to the toxicity and antitumor activity of chemotherapeutic regimens for MDR reversal, and should result in improved therapeutic specificity and efficacy.59

Received 26 July 2000; Revised 16 August 2000;Accepted 17 August 2000; Published online 9 November 2000 Correspondence to: K. Nooter, Rotterdam Cancer Institute/University Hospital Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam,The Netherlands. Tel: +31 10 408 8357; Fax: +31 10 408 8363; E-mail: [email protected]

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