抄録
Background
Cytochrome P450 (CYP) gene polymorphisms affect enzyme activity and are a major determinant of inter-individual differences in pharmacokinetics. However, the response to CYP inducers or inhibitors according to CYP genotype remains unclear. In this study, we investigated the effects of CYP inducers and inhibitors on CYP2C19 enzyme activity according to genotype and basal enzyme activity.
Methods
Nineteen healthy Japanese subjects were enrolled in this study. CYP2C19 genotypes were determined using the TaqMan method. The concentration of omeprazole and 5'-hydroxyomeprazole, which is produced from omeprazole by CYP2C19, was determined under basal conditions and after administration of rifampicin (a CYP inducer) and fluvoxamine (a CYP inhibitor) in a 4-h plasma sample using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were estimated by non-compartmental analysis from the concentration-time profile in plasma. CYP2C19 enzyme activity was assessed using omeprazole/5-hydroxyomeprazole concentration ratios. Changes in CYP enzyme activity were determined by comparing enzyme activity after administration of rifampicin or fluvoxamine as the numerator and basal activity as the denominator.
Results
The frequencies of subjects with CYP2C19*1/*1, CYP2C19*1/*2, CYP2C19*1/*3, CYP2C19*2/*2, and CYP2C19*2/*3 alleles were 52.6%, 21.0%, 5.3%, 10.5%, and 10.5%, respectively. Omeprazole/5-hydroxyomeprazole concentration ratios under basal conditions and after the administration of rifampicin and fluvoxamine are shown in Table. Basal CYP2C19 enzyme activity in subjects with CYP2C19*2/*2 or CYP2C19*2/*3 alleles was lower than that in subjects with a CYP2C19*1 allele. After the administration of rifampicin, CYP2C19 activity was induced in all genotypes and there was no significant difference in the change of enzyme activity according to CYP genotype. Conversely, changes in enzyme activity following fluvoxamine treatment were greater in subjects with CYP2C19*1/*1 alleles than in those with CYP2C19*2/*2 or CYP2C19*2/*3 alleles (p<0.05).
Conclusion
Fluvoxamine significantly inhibited the CYP2C19 enzyme according to genotype.
