Effects of the CYP3A5 genotype on omeprazole sulfoxidation in CYP2C19PMs

Objective Omeprazole is metabolized by the two cytochrome P450 isoforms, CYP3A ( sulfoxidation) and CYP2C19 ( hydroxydation). The aim of this study was to determine whether the CYP3A5 genotype is an important determinant of inter- individual variability of total CYP3A activity in vivo. Methods Plasma levels of omeprazole and omeprazole sulfone were analyzed by high- performance liquid chromatography in blood samples drawn 4 - 5 h after 43 CYP2C19 poor metabolizers ( PMs) had ingested a single oral 40 mg dose of omeprazole. The CYP3A5* 3 allele was identified using a PCR- restriction fragment length polymorphism assay. Results Among the 43 CYP2C19 PMs, 24 were CYP3A5*3/*3 carriers and 19 were CYP3A5* 1 carriers ( CYP3A5*1/*1 in one subject and CYP3A5* 1/* 3 in 18 subjects). No significant difference was found between the mean log10( metabolic ratio) of the CYP3A5* 3/* 3 carriers ( 0.314 +/- 0.369) and CYP3A5* 1 carriers ( 0.330 +/- 0.313). Conclusions The CYP3A5 genotype was not an important factor underlying the inter- individual variation in the metabolic ratio of omeprazole to omeprazole sulfone in our study cohort, although genotype can be considered to be responsible for the inter- individual variation of many CYP3A substrates in vivo.