Influence of Cytochrome P450 (CYP)??3A5 Polymorphisms on the Pharmacokinetics of Lansoprazole Enantiomers in CYP2C19 Extensive Metaboliser Renal Transplant Recipients

Abstract

Lansoprazole is extensively metabolised by cytochrome P450 (CYP) 2C19 and CYP3A4. The purpose of this study was to evaluate the effects of CYP3A5 polymorphism (A6986G) on the pharmacokinetics of lansoprazole enantiomers in renal transplant recipients who are CYP2C19 extensive metabolisers (EMs). Among 40 Japanese CYP2C19 EMs, 20 had the CYP3A5*1 allele (*1/*1 in two subjects and *1/*3 in 18 subjects) and 20 had the CYP3A5*3/*3 genotype. After repeated oral doses of racemic lansoprazole 30mg once daily for 28 days, plasma concentrations of lansoprazole enantiomers were determined using high performance liquid chromatography. The mean area under the plasma concentration-time curves from 0 to infinity (AUC(infinity)) of (R)- and (S)-lansoprazole in recipients with the CYP3A5*1 allele were 3145 and 384 ng * h/mL, respectively, compared with 4218 and 587 ng * h/mL in recipients with the CYP3A5*3/*3 genotype. The AUC(infinity) and the maximum plasma concentration of (R)- and (S)-lansoprazole in subjects with the CYP3A5*3/*3 genotype were greater than subjects with CYP3A5*1/*1 + *1/*3 alleles. The mean R/S ratio for AUC of lansoprazole in each CYP3A5 genotype group was the same (12.6). Our findings show that CYP3A5 genotype is not an important determinant of enantioselective disposition of lansoprazole. Based on our results and those of previous studies, the enantioselective disposition of lansoprazole appears to be primarily influenced by enantioselective metabolism by CYP2C19 rather than by CYP3A.