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Effects of CYP3A5 and CYP2D6 Genetic Polymorphism on the Pharmacokinetics of Diltiazem and Its Metabolites in Chinese Subjects

Effects of CYP3A5 and CYP2D6 Genetic Polymorphism on the Pharmacokinetics of Diltiazem and Its Metabolites in Chinese Subjects

T Zheng, C H Su, J Zhao, X J Zhang, T Y Zhang, L R Zhang, Q C Kan, S J Zhang

Pharmazie. 2013 Apr;68(4):257-60.

PMID: 23700791

Abstract:

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(o-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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP23515459	Desacetyl diltiazem hydrochloride		23515-45-9	Price

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