CYP3A5 genotype does not influence everolimus in vitro metabolism and clinical pharmacokinetics in renal transplant recipients

Abstract

Background: CYP3A5 genotyping might be useful to guide tacrolimus and sirolimus dosing. The aim of this study was to assess the influence of CYP3A5 polymorphism on everolimus metabolism and pharmacokinetics.

Methods: We investigated the effect of CYP3A5 6986A>G polymorphism (CYP3A5*1/*3 alleles) on the pharmacokinetics of everolimus in 28 renal transplant patients and on its in vitro hepatic metabolism using a bank of genotyped human liver microsomes (n=49). We further evaluated in vitro the contribution of CYP3A4, CYP3A5, and CYP2C8 to everolimus hepatic metabolism using recombinant enzymes.

Results: We found no association between CYP3A5 polymorphism and everolimus pharmacokinetics in renal transplant patients. On the other hand, no effect of CYP3A5 polymorphism was observed on the intrinsic clearance of everolimus by human liver microsomes, whereas that of tacrolimus (positive control) was 1.5-fold higher in microsomes carrying the CYP3A5*1 allele than in noncarriers. In vitro data showed that CYP3A4 is a better catalyst of everolimus metabolism than CYP3A5, whereas the opposite was observed for tacrolimus.

Conclusions: This study provides direct and indirect evidence that CYP3A5 genotyping cannot help improve everolimus therapy.

Figure 1

Mean ± SD of dose-normalized concentration-time profiles of everolimus as a function of the CYP3A5 genotype (CYP3A5*1/*3: n=7; CYP3A5*3/*3: n= 21).

Figure 2

Estimated in vitro intrinsic clearance (CL_int) of everolimus (a) and tacrolimus (b) metabolism by human recombinant cytochrome P450 (rhCYP) 3A4 and 3A5. Grayed box represents the activity of rhCYP co-expressed with cytochrome b5 and hatched box the activity of rhCYP without cytochrome b5. The CL_int were estimated from tacrolimus and everolimus in vitro metabolic half-lives as described in the materials and methods section. Results are derived from duplicate experiments.