Effects of CYP3A5 and CYP2D6 genetic polymorphism on the pharmacokinetics of diltiazem and its metabolites in Chinese subjects

Purpose: To assess the possibility of using CYP2D6*10 + CYP3A5*3 as biomarkers to predict the pharmacokinetics of diltiazem and its two metabolites among healthy Chinese subjects. Methods: 41 healthy Chinese were genotyped for CYP3A5*3 and CYP2D6*10, and then received a single oral dose of diltiazem hydrochloride capsules (300 mg). Multiple blood samples were collected over 48 h, and the plasma concentrations of diltiazem, N-desmethyl diltiazem and desacetyl diltiazem were determined by HPLC-MS/MS. The relationships between the genotypes and pharmacokinetics were investigated. Results: The pharmacokinetics of diltiazem, N-desmethyl diltiazem were not significantly affected by both CYP3A5*3 and CYP2D6*10 alleles. However, the systemic exposure of the pharmacologyically active metabolites, desacetyl diltiazem, was 2-fold higher in CYP2D6*10/*10 genotype carriers than in *1/*10 or *1/*1 ones (AUC_(0–inf) of CYP2D6*1/*1, *1/*10 and *10/*10 are 398.2 ± 162.9, 371.0 ± 69.2 and 726.2 ± 468.1 respectively, p < 0.05). Conclusions: Two of the most frequent alleles, CYP3A5*3 and CYP2D6*10, among Chinese do not have major impacts on the disposition of diltiazem and N-desmethyl diltiazem. However, the desacetyl diltiazem showed 2-fold accumulation in individuals with CYP2D6*10/*10 genotype. Despite this, the effect of genotype of CYP2D6 on clinical outcome of diltiazem treatment is expected to be limited.