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CYP2C19 genotypes and omeprazole metabolism after single and repeated dosing when combined with clarithromycin
1Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Objectives:
Omeprazole is metabolized mainly by CYP2C19 which has two major mutations (CYP2C19*2 in exon5 and CYP2C19*3 in exon4) associated with the poor metabolizer (PM) phenotype. The aim of this study was to examine the relationship between genetic polymorphism of CYP2C19 and metabolism of omeprazole administrated as a single dose or as repeated-doses, which were in both cases co-administered 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 omeprazole and 400 mg clarithromycin to six healthy Japanese 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 omeprazole 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 x h(-1) x ml(-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) ng x h(-1) x ml(-1), respectively. The ratios of AUCs of omeprazole/5-hydroxyomeprazole for *1/*1, * 1/*2 or * 1/*3 and *2/*3 were7, 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 differences 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 genotypes in the repeated-dose study had lower CYP2C19 activity than subjects of the same genotype in the single-dose study. The difference in omeprazole metabolism between subjects with different genotypes observed on day 1 seemed to disappear after 7 days of repeated-dose administration.
Insights
Genetic variations in CYP2C19 significantly impact omeprazole metabolism. Repeated dosing of omeprazole with clarithromycin alters drug metabolism, with differences between genotypes diminishing over time.
Area of Science:
- Pharmacogenomics
- Drug Metabolism
- Cytochrome P450 Enzymes
Background:
- Omeprazole metabolism is primarily mediated by CYP2C19.
- CYP2C19 exhibits genetic polymorphisms, notably CYP2C19*2 and CYP2C19*3, linked to poor metabolizer phenotypes.
- Understanding these genetic variations is crucial for predicting drug response.
Purpose of the Study:
- To investigate the relationship between CYP2C19 genetic polymorphism and omeprazole metabolism.
- To compare omeprazole metabolism after single-dose versus repeated-dose administration with clarithromycin.
Main Methods:
- Twelve healthy Japanese subjects were genotyped for CYP2C19 polymorphisms.
- Plasma omeprazole and metabolite levels were measured after single and repeated oral doses of omeprazole and clarithromycin.
Main Results:
- Single-dose study revealed significant differences in omeprazole AUC based on CYP2C19 genotype (*1/*1, *1/*2, *1/*3, *2/*3).
- Repeated-dose study showed altered omeprazole AUC and 5-hydroxyomeprazole ratios compared to single-dose, with genotype-specific variations.
- Differences in omeprazole AUC and Cmax were observed between single and repeated doses, with some genotype-specific effects diminishing over the 7-day period.
Conclusions:
- Repeated-dose administration of omeprazole with clarithromycin led to reduced CYP2C19 activity in subjects with *1/*1, *1/*2, and *1/*3 genotypes compared to single-dose administration.
- The observed differences in omeprazole metabolism based on CYP2C19 genotype appeared to normalize after 7 days of repeated-dose administration.