BACKGROUND: The cytochrome P450 (CYP) 3A subfamily plays an important role in the metabolism of various endogenous and exogenous compounds. Among CYP3A subfamily members, CYP3A5 is polymorphically expressed and the CYP3A5*3 and CYP3A5*6 alleles are known not to express functional CYP3A5. Thus, these mutant alleles are thought to be responsible for interindividual variability of CYP3A activity. METHODS: Subjects possessing CYP3A5*1/*1, *1/*3 or *3/*3 received oral administration of diltiazem hydrochloride (60 mg), and plasma and urinary concentrations of diltiazem and its metabolite N-desmethyldiltiazem were measured. Before drug intake, cortisol metabolic clearance in each subject was measured to estimate in vivo CYP3A4 activity. RESULTS: The mean values of total oral diltiazem clearance of subjects with *1/*1, *1/*3 and *3/*3 were 183.4 +/- 39.4, 197.9 +/- 49.6 and 293.6 +/- 141.1 (l/h), respectively, and were not significantly different among the 3 genotype groups. The cortisol metabolic clearance was not significantly different among the three genotype groups, indicating that the CYP3A4 activity is not significantly different. CONCLUSION: The results suggest that CYP3A5*3 has only a minor effect on the pharmacokinetics and metabolism of diltiazem. Although our results did not indicate significance of CYP3A5, the effects of CYP3A5*3 on the metabolism of other CYP3A substrates remain to be investigated.
BACKGROUND: The cytochrome P450 (CYP) 3A subfamily plays an important role in the metabolism of various endogenous and exogenous compounds. Among CYP3A subfamily members, CYP3A5 is polymorphically expressed and the CYP3A5*3 and CYP3A5*6 alleles are known not to express functional CYP3A5. Thus, these mutant alleles are thought to be responsible for interindividual variability of CYP3A activity. METHODS: Subjects possessing CYP3A5*1/*1, *1/*3 or *3/*3 received oral administration of diltiazem hydrochloride (60 mg), and plasma and urinary concentrations of diltiazem and its metabolite N-desmethyldiltiazem were measured. Before drug intake, cortisol metabolic clearance in each subject was measured to estimate in vivo CYP3A4 activity. RESULTS: The mean values of total oral diltiazem clearance of subjects with *1/*1, *1/*3 and *3/*3 were 183.4 +/- 39.4, 197.9 +/- 49.6 and 293.6 +/- 141.1 (l/h), respectively, and were not significantly different among the 3 genotype groups. The cortisol metabolic clearance was not significantly different among the three genotype groups, indicating that the CYP3A4 activity is not significantly different. CONCLUSION: The results suggest that CYP3A5*3 has only a minor effect on the pharmacokinetics and metabolism of diltiazem. Although our results did not indicate significance of CYP3A5, the effects of CYP3A5*3 on the metabolism of other CYP3A substrates remain to be investigated.