PHARMACOKINETICS AND DISPOSITION

Objectives: Omeprazole is metabolized mainly by CYP2C19 which has two major mutations (CYP2C19*2 in exon5 and CYP2C19*3 in exon4) as- sociated with the poor metabolizer (PM) phenotype. The aim of this study was to examine the relationship be- tween genetic polymorphism of CYP2C19 and metabo- lism of omeprazole administrated as a single dose or as repeated-doses, which were in both cases co-adminis- tered with clarithromycin. Methods: Twelve healthy Japanese subjects were typed for CYP2C19 polymorphism. In the single-dose study, plasma levels of omeprazole and its metabolites were measured for 24 h after administration of 20 mg ome- prazole and 400 mg clarithromycin to six healthy Japa- nese subjects. In the repeated-dose study, plasma levels of omeprazole and its metabolites were measured after repeated oral administration of 20 mg omeprazole and 400 mg clarithromycin twice daily for 6 days and then after 20 mg omeprazole and 400 mg clarithromycin once on the 7th day to the other 6 healthy Japanese subjects. Results: In the single-dose study, the areas under the plasma concentration-versus-time curve (AUCs) of om- eprazole of homozygotes for the wild-type allele (*1/*1 n = 2), heterozygotes (n = 3) for the CYP2C19*2 (*1/ *2) or for the CYP2C19*3 (*1/*3) and heterozygote (n = 1) for the two defects (*2/*3) were on average 450, 1007 and 6710 ng AEh )1 AEml )1 , respectively. The ratios of AUCs of omeprazole/5-hydroxyomeprazole for *1/*1, *1/*2 or *1/*3 and *2/*3 were 1, 2 and 30, respectively. In the repeated-dose study, the AUCs of omeprazole for *1/ *1, *1/*2 or *1/*3 and *2/*3 were 4041 (n = 2), 3149 (n = 3) and 6684 (n =1 ) ngAEh )1 AEml )1 , respectively. The ratios of AUCs of omeprazole/5-hydroxyomepra- zole for *1/*1, *1/*2 or *1/*3 and *2/*3 were 7, 11 and 30, respectively. In the repeated-dose study, the AUC of omeprazole of *1/*1 genotypes was nine-fold higher, that of *1/*2 and *1/*3 genotypes was three-fold higher, and the Cmax value of omeprazole was three-fold higher compared with subjects with the same genotype in the single-dose study. However, there were few diAerences in the AUC and Cmax of omeprazole between the *2/*3 genotype in the single-dose study and the homozygote for the CYP2C19*2 (*2/*2) in the repeated-dose study. Conclusion: Subjects with *1/*1, *1/*2 and *1/*3 geno- types in the repeated-dose study had lower CYP2C19 activity than subjects of the same genotype in the single- dose study. The diAerence in omeprazole metabolism between subjects with diAerent genotypes observed on day 1 seemed to disappear after 7 days of repeated-dose administration.