Efavirenz-mediated induction of omeprazole metabolism is CYP2C19 genotype dependent

Abstract

Efavirenz increases CYP2C19- and CYP3A-mediated omeprazole metabolism. We hypothesized that CYP2C19 and CYP2B6 genetic polymorphisms influence the extent of induction of omeprazole metabolism by efavirenz. Healthy subjects (n=57) were administered a single 20 mg oral dose of omeprazole on two occasions: with a single 600 mg efavirenz dose; and after a 17-day treatment with efavirenz (600 mg per day). DNA was genotyped for CYP2C19*2, *3 and *17 alleles and CYP2B6*6, *4 and *9 alleles using Taqman assays. Omeprazole, its enantiomers and metabolites were measured by liquid chromatography/tandem mass spectrometry. Our results showed that efavirenz increased omeprazole clearances in all CYP2C19 genotypes in non-stereoselective manner, but the magnitude of induction was genotype dependent. Metabolic ratios of 5-hydroxylation of omeprazole were reduced in extensive and intermediate metabolizers of CYP2C19 (P<0.05). No significant associations were observed between CYP2B6 genotypes and induction by efavirenz on omeprazole metabolism. Our data indicate how interplays between drug interactions and CYP2C19 genetic variations may influence systemic exposure of CYP2C19 substrates.

Figure 1

CYP2C19 phenotype frequency distribution of the log metabolic indexes of hydroxylation (A-C) and sulfoxidation (D) of omeprazole after a single 600 mg oral dose of efavirenz or during induction by multiple doses (600 mg/day for 17 days) of efavirenz. Racemic (A), R-omeprazole (B) and S-omeprazole (C) hydroxylation metabolic indexes are presented. The histograms were plotted using the log of omeprazole concentration divided by the metabolite concentration (5-hydroxyomeprazole or omeprazole sulfone) taken 3 hours after the administration of omeprazole. The probit plots were obtained by curve fitting of the log of omeprazole hydroxylation and sulfoxidation metabolic index from 57 subjects.

Figure 2

Association of CYP2C19 genotypes with omeprazole clearances when coadministered with a single dose or after multiple doses of efavirenz. Box plots of the clearance of A) racemate, B) R-omeprazole and C) S-omeprazole after single and multiple doses of efavirenz according to the CYP2C19 genotype status; ultra-rapid (UM; CYP2C19*17*17), extensive (EM; CYP2C19*1*1, CYP2C19*1*17), intermediate (CYP2C19*1*2 or *3) metabolizers. One-way ANOVA with Dunn’s comparison statistical analysis was performed to compare clearances between genotype groups and paired t-test was used to compare single dose vs. multiple doses for each individual genotype (*p<0.05 and **p<0.001).

Figure 3

Effects of CYP2B6 genetic polymorphisms on the log hydroxylation and sulfoxidation metabolic indexes of omperazole are presented after a single and multiple doses of efavirenz. The result showed that no significant difference was observed between all CYP2B6 genotype groups. One-way ANOVA with Dunn’s comparison statistical analysis was performed to compare log metabolic index between CYP2B6 genotype groups and paired t-test was used to compare single dose vs. multiple doses for each individual genotype. Percent changes (mean ±SD) of the log metabolic index for the A) 5-hydroxylation and B) sulfoxidation of omeprazole are presented, and no difference was observed between the CYP2B6 genotypes.