Research Article

Impact of CYP3A5 genotype on tacrolimus versus midazolam clearance in renal transplant recipients: new insights in CYP3A5-mediated drug metabolism

Department of Nephrology & Renal Transplantation, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium

Laboratory of Nephrology, KU Leuven, Leuven, Belgium

Translational Research Center for Gastrointestinal Disorders (TARGID) & Leuven Food Science & Nutrition Research Centre (LFoRCe), KU Leuven, Leuven, Belgium

Search for more papers by this author

Yves Vanrenterghem

Department of Nephrology & Renal Transplantation, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium

Search for more papers by this author

Dirk RJ Kuypers

* Author for correspondence

Department of Nephrology & Renal Transplantation, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium.

Search for more papers by this author

Email the corresponding author at dirk.kuypers@uzleuven.be

Published Online:11 Sep 2013https://doi.org/10.2217/pgs.13.133

View article

Abstract

Background & aim:In vitro studies have identified both midazolam and tacrolimus as dual CYP3A4 and CYP3A5 substrates. In vivo; however, the CYP3A5 genotype has a marked impact on tacrolimus pharmacokinetics, whereas it seems not to affect midazolam pharmacokinetics. The aim of the current study was to explore this paradigm in a relevant clinical setting. Patients & methods: A case–control study in 80 tacrolimus-treated renal transplant recipients comparing systemic and apparent oral midazolam clearance and tacrolimus pharmacokinetics in CYP3A5 expressers (CYP3A5*1 allele carriers) and CYP3A5 nonexpressers (CYP3A5*3/*3) was performed. Results: CYP3A5 expressers display an approximately 2.4-fold higher tacrolimus clearance as compared with CYP3A5 nonexpressers, whereas there are no differences in systemic and apparent oral midazolam clearance. Conclusion: These data confirm that in vivo CYP3A5 plays an important role in tacrolimus metabolism, while its contribution to midazolam metabolism in a relevant study population is limited. Furthermore, these data suggest that midazolam is to be considered as a phenotypic probe for in vivo CYP3A4 activity rather than combined CYP3A4 and CYP3A5 activity.

Original submitted 12 March 2013; Revision submitted 10 July 2013

Keywords:

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

References

1 Guengerich FP. Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu. Rev. Pharmacol. Toxicol.39,1–17 (1999).Crossref, Medline, CAS, Google Scholar
2 Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit. Rev. Toxicol.22,1–21 (1992).Crossref, Medline, CAS, Google Scholar
3 Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet360,1155–1162 (2002).Crossref, Medline, CAS, Google Scholar
4 Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T. Expression of CYP3A in the human liver – evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur. J. Biochem.247,625–634 (1997).Crossref, Medline, CAS, Google Scholar
5 Westlind A, Malmebo S, Johansson I et al. Cloning and tissue distribution of a novel human cytochrome p450 of the CYP3A subfamily, CYP3A43. Biochem. Biophys. Res. Commun.281,1349–1355 (2001).Crossref, Medline, CAS, Google Scholar
6 Lamba JK, Lin YS, Schuetz EG, Thummel KE. Genetic contribution to variable human CYP3A-mediated metabolism. Adv. Drug Deliv. Rev.54,1271–1294 (2002).▪ Comprehensive review of the impact of genetic variation in the genes encoding CYP3A isoenzymes on CYP3A-mediated metabolism.Crossref, Medline, CAS, Google Scholar
7 Kuehl P, Zhang J, Lin Y et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat. Genet.27,383–391 (2001).▪▪ First study describing the genetic basis for polymorphic CYP3A5 expression.Crossref, Medline, CAS, Google Scholar
8 Schuetz EG, Relling MV, Kishi S et al. PharmGKB update: II. CYP3A5, cytochrome P450, family 3, subfamily A, polypeptide 5. Pharmacol. Rev.56,159 (2004).Crossref, Medline, CAS, Google Scholar
9 Niwa T, Murayama N, Emoto C, Yamazaki H. Comparison of kinetic parameters for drug oxidation rates and substrate inhibition potential mediated by cytochrome P450 3A4 and 3A5. Curr. Drug Metab.9,20–33 (2008).Crossref, Medline, CAS, Google Scholar
10 Lin YS, Dowling AL, Quigley SD et al. Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. Mol. Pharmacol.62,162–172 (2002).Crossref, Medline, CAS, Google Scholar
11 Westlind-Johnsson A, Malmebo S, Johansson A et al. Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism. Drug Metab. Dispos.31,755–761 (2003).Crossref, Medline, CAS, Google Scholar
12 Yamaori S, Yamazaki H, Iwano S et al. CYP3A5 contributes significantly to CYP3A-mediated drug oxidations in liver microsomes from Japanese subjects. Drug Metab. Pharmacokinet.19,120–129 (2004).Crossref, Medline, CAS, Google Scholar
13 Williams JA, Ring BJ, Cantrell VE et al. Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab. Dispos.30,883–891 (2002).Crossref, Medline, CAS, Google Scholar
14 Dai Y, Hebert MF, Isoherranen N et al. Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro. Drug Metab. Dispos.34,836–847 (2006).▪ In vitro study demonstrating that CYP3A5 contributes significantly to the metabolic clearance of tacrolimus.Crossref, Medline, CAS, Google Scholar
15 Kamdem LK, Streit F, Zanger UM et al. Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin. Chem.51,1374–1381 (2005).▪ In vitro study demonstrating that CYP3A5 contributes significantly to the metabolic clearance of tacrolimus.Crossref, Medline, CAS, Google Scholar
16 MacPhee IA, Fredericks S, Tai T et al. Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome p4503A5 and P-glycoprotein correlate with dose requirement. Transplantation74,1486–1489 (2002).▪▪ First in vivo study reporting a major impact of genetically determined CYP3A5 expression on tacrolimus pharmacokinetics in renal transplant recipients.Crossref, Medline, CAS, Google Scholar
17 Hesselink DA, van Schaik RH, van der Heiden IP et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin. Pharmacol. Ther.74,245–254 (2003).Crossref, Medline, CAS, Google Scholar
18 Kuypers DR, de Jonge H, Naesens M, Lerut E, Verbeke K, Vanrenterghem Y. CYP3A5 and CYP3A4 but not MDR1 single-nucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxicity in renal recipients. Clin. Pharmacol. Ther.82,711–725 (2007).Crossref, Medline, CAS, Google Scholar
19 Goto M, Masuda S, Kiuchi T et al. CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation. Pharmacogenetics14,471–478 (2004).Crossref, Medline, CAS, Google Scholar
20 Floyd MD, Gervasini G, Masica AL et al. Genotype–phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European– and African–American men and women. Pharmacogenetics13,595–606 (2003).Crossref, Medline, CAS, Google Scholar
21 Eap CB, Buclin T, Hustert E et al. Pharmacokinetics of midazolam in CYP3A4- and CYP3A5-genotyped subjects. Eur. J. Clin. Pharmacol.60,231–236 (2004).Medline, CAS, Google Scholar
22 Yu KS, Cho JY, Jang IJ et al. Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states. Clin. Pharmacol. Ther.76,104–112 (2004).Crossref, Medline, CAS, Google Scholar
23 He P, Court MH, Greenblatt DJ, von Moltke LL. Genotype–phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin. Pharmacol. Ther.77,373–387 (2005).Crossref, Medline, CAS, Google Scholar
24 Kharasch ED, Walker A, Isoherranen N et al. Influence of CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of the cytochrome P4503A probes alfentanil and midazolam. Clin. Pharmacol. Ther.82,410–426 (2007).Crossref, Medline, CAS, Google Scholar
25 Miao J, Jin Y, Marunde RL et al. Association of genotypes of the CYP3A cluster with midazolam disposition in vivo. Pharmacogenomics J.9,319–326 (2009).Crossref, Medline, CAS, Google Scholar
26 Halama B, Hohmann N, Burhenne J, Weiss J, Mikus G, Haefeli WE. A nanogram dose of the CYP3A probe substrate midazolam to evaluate drug interactions. Clin. Pharmacol. Ther.93,564–571 (2013).Crossref, Medline, CAS, Google Scholar
27 de Loor H, de Jonge H, Verbeke K, Vanrenterghem Y, Kuypers DR. A highly sensitive liquid chromatography tandem mass spectromety method for simultaneous quantification of midazolam, 1´-hydroxymidazolam and 4-hydroxymidazolam in human plasma. Biomed. Chromatogr.25,1091–1098 (2011).Crossref, Medline, CAS, Google Scholar
28 de Jonge H, de Loor H, Verbeke K, Vanrenterghem Y, Kuypers DR. In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients. Clin. Pharmacol. Ther.90,414–422 (2011).Crossref, Medline, CAS, Google Scholar
29 Napoli KL, Hammett-Stabler C, Taylor PJ et al. Multi-center evaluation of a commercial kit for tacrolimus determination by LC/MS/MS. Clin. Biochem.43,910–920 (2010).Crossref, Medline, CAS, Google Scholar
30 Tateishi T, Watanabe M, Moriya H, Yamaguchi S, Sato T, Kobayashi S. No ethnic difference between Caucasian and Japanese hepatic samples in the expression frequency of CYP3A5 and CYP3A7 proteins. Biochem. Pharmacol.57,935–939 (1999).Crossref, Medline, CAS, Google Scholar
31 Goh BC, Lee SC, Wang LZ et al. Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. J. Clin. Oncol.20,3683–3690 (2002).Crossref, Medline, CAS, Google Scholar
32 Wong M, Balleine RL, Collins M, Liddle C, Clarke CL, Gurney H. CYP3A5 genotype and midazolam clearance in Australian patients receiving chemotherapy. Clin. Pharmacol. Ther.75,529–538 (2004).Crossref, Medline, CAS, Google Scholar
33 Thummel KE. Does the CYP3A5*3 polymorphism affect in vivo drug elimination? Pharmacogenetics13,585–587 (2003).Crossref, Medline, Google Scholar
34 Burk O, Schwab M. The limited impact of CYP3A5 genotype for the pharmacokinetics of CYP3A substrates. Eur. J. Clin. Pharmacol.63,1097–1098 (2007).Crossref, Medline, Google Scholar
35 Jacobson PA, Oetting WS, Brearley AM et al. Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium. Transplantation91,300–308 (2011).▪▪ Large-scale assessment of the effect of 2722 SNPs on tacrolimus exposure in 695 renal transplant recipients, confirming the major impact of the CYP3A5 genotype on tacrolimus pharmacokinetics.Crossref, Medline, CAS, Google Scholar
36 Perera MA. The missing linkage: what pharmacogenetic associations are left to find in CYP3A? Expert Opin. Drug Metab. Toxicol.6,17–28 (2010).Crossref, Medline, CAS, Google Scholar
37 Elens L, van Schaik RH, Panin N et al. Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitors’ dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenomics12,1383–1396 (2011).Link, CAS, Google Scholar
38 Elens L, Nieuweboer A, Clarke SJ et al. CYP3A4 intron 6 C>T SNP (CYP3A4*22) encodes lower CYP3A4 activity in cancer patients, as measured with probes midazolam and erythromycin. Pharmacogenomics14,137–149 (2013).Link, CAS, Google Scholar
39 Naesens M, Lerut E, de Jonge H, van Damme B, Vanrenterghem Y, Kuypers DR. Donor age and renal P-glycoprotein expression associate with chronic histological damage in renal allografts. J. Am. Soc. Nephrol.20,2468–2480 (2009).Crossref, Medline, Google Scholar
40 de Jonge H, Kuypers DR. Pharmacogenetics in solid organ transplantation: current status and future directions. Transplant. Rev. (Orlando)22,6–20 (2008).Crossref, Medline, Google Scholar
41 Gan TJ. Pharmacokinetic and pharmacodynamic characteristics of medications used for moderate sedation. Clin. Pharmacokinet.45,855–869 (2006).Crossref, Medline, CAS, Google Scholar
42 Nordt SP, Clark RF. Midazolam: a review of therapeutic uses and toxicity. J. Emerg. Med.15,357–365 (1997).Crossref, Medline, CAS, Google Scholar
43 Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: pharmacology and uses. Anesthesiology62,310–324 (1985).Crossref, Medline, CAS, Google Scholar
44 Moller A, Iwasaki K, Kawamura A et al. The disposition of 14C-labeled tacrolimus after intravenous and oral administration in healthy human subjects. Drug Metab. Dispos.27,633–636 (1999).▪ Study in healthy volunteers using radiolabeled tacrolimus providing detailed information on tacrolimus disposition.Medline, CAS, Google Scholar
45 Kim RB, Wandel C, Leake B et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm. Res.16,408–414 (1999).Crossref, Medline, CAS, Google Scholar
46 Herbert MF. Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv. Drug Deliv. Rev.27,201–214 (1997).Crossref, Medline, Google Scholar
47 Wu CY, Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm. Res.22,11–23 (2005).Crossref, Medline, CAS, Google Scholar
48 Cummins CL, Jacobsen W, Benet LZ. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J. Pharmacol. Exp. Ther.300,1036–1045 (2002).Crossref, Medline, CAS, Google Scholar
49 Benet LZ, Cummins CL, Wu CY. Unmasking the dynamic interplay between efflux transporters and metabolic enzymes. Int. J. Pharm.277,3–9 (2004).Crossref, Medline, CAS, Google Scholar
50 Benet LZ. The drug transporter-metabolism alliance: uncovering and defining the interplay. Mol. Pharm.6,1631–1643 (2009).Crossref, Medline, CAS, Google Scholar
51 Thummel KE, O’Shea D, Paine MF et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin. Pharmacol. Ther.59,491–502 (1996).Crossref, Medline, CAS, Google Scholar
52 Uesugi M, Masuda S, Katsura T, Oike F, Takada Y, Inui K. Effect of intestinal CYP3A5 on postoperative tacrolimus trough levels in living-donor liver transplant recipients. Pharmacogenet. Genomics16,119–127 (2006).Crossref, Medline, CAS, Google Scholar
53 Thummel KE, Shen DD, Podoll TD et al. Use of midazolam as a human cytochrome P450 3A probe: I. In vitro–in vivo correlations in liver transplant patients. J. Pharmacol. Exp. Ther.271,549–556 (1994).▪ Pivotal trial exploring the use of midazolam as a drug probe to assess in vivo CYP3A activity.Medline, CAS, Google Scholar
54 Gorski JC, Jones DR, Haehner-Daniels BD, Hamman MA, O’Mara EM, Hall SD. The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clin. Pharmacol. Ther.64,133–143 (1998).Crossref, Medline, CAS, Google Scholar
55 Tsunoda SM, Velez RL, von Moltke LL, Greenblatt DJ. Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole. Clin. Pharmacol. Ther.66,461–471 (1999).Crossref, Medline, CAS, Google Scholar
101 EudraCT. https://eudract.ema.europa.euGoogle Scholar

Vol. 14, No. 12

Supplemental Materials

Metrics

Downloaded 253 times

History

Published online 11 September 2013

Published in print September 2013

Information

Keywords

Acknowledgements

The authors thank our trial nurses C Beerten, M Dubois, I Laenen, A Swinnen and H Wielandt for their great efforts in this study, and A Herelixka for managing the clinical database. The authors also thank M Dekens, K Vandormael, E Vanhalewyck and K Verstraete of the laboratory of Nephrology for their excellent technical assistance. The continued support of all colleagues of the Leuven Collaborative Group for Renal Transplantation is much appreciated. Last but certainly not least special thanks to all renal transplant recipients who participated in this study.

Financial & competing interest disclosure

H de Jonge and D Kuypers received a grant from the Fund for Scientific Research Flanders (FWO Vlaanderen). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

PDF download