The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients

Charles R. Yates, Wenhui Zhang, Pengfei Song, Shen Li, A. Osama Gaber, Malak Kotb, Marsha R. Honaker, Rita R. Alloway, Bernd Meibohm

Research output: Contribution to journalArticle

161 Scopus citations

Abstract

Variability in CYP3A (CYP3A4/5) and P-glycoprotein (human MDR1 gene product) activity underlies interindividual differences in oral cyclosporine (CsA) bioavailability. Racial differences in polymorphic expression of CYP3A5 und MDR1 may explain observed interracial variability in oral bioavailability. Our objective was to evaluate the effect of CYP3A5 and MDR1 polymorphic expression on CsA oral disposition. Steady-state plasma concentration profiles (n = 19) were sampled in renal transplant recipients receiving concentration-adjusted CsA maintenance therapy. CsA plasma concentrations were measured by fluorescence polarization immunoassay. CYP3A5 and MDR1 genotypes were determined by real-time polymerase chain reaction. Noncompartmental pharmacokinetic analysis and nonlinear mixed-effects modeling (NONMEM) were performed to assess the effect of genotype on CsA pharmacokinetics. MDR1 C3435T genotype was identified as the best predictor of CsA systemic exposure. CsA oral clearance was significantly higherin subjects who carried atleast one 3435T allele compared to homozygous wild-type individuals (40.0 ± 2.2 vs. 26.4 ± 3.1 L/h, p = 0.007). MDR1 C3435T genotype accounted for 43% of the interindividual variability of CsA oral clearance in the study population after accounting for interoccasion variability. The authors were unable to independently assess whether CYP3A5 correlated with any CsA pharmacokinetic parameter since all CYP3A5 nonexpressors were also 3435T allele carriers. MDR1 3435T allele carriers have enhanced oral clearance compared to individuals with the CC genotype. The frequency of the 3435T allele is lower in African Americans compared to Caucasians. Thus, the MDR1 C3435T genotype offers a potential mechanistic basis to explain interracial differences in CsA oral bioavailability. Further studies are needed to explore the relationship between CYP3A5 and MDR1 genotype and phenotype.

Original languageEnglish (US)
Pages (from-to)555-564
Number of pages10
JournalJournal of Clinical Pharmacology
Volume43
Issue number6
DOIs
StatePublished - Jun 1 2003

Keywords

  • Cyclosporine
  • Cytochrome P-450 3A5
  • P-glycoprotein
  • Pharmacogenetics
  • Pharmacokinetics
  • Single nucleotide polymorphism
  • Transplantation

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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