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Influence of ABCB1 gene polymorphisms on the pharmacokinetics of verapamil among healthy Chinese Han ethnic subjects
Author(s) -
Zhao LiMei,
He XiaoJing,
Qiu Feng,
Sun YaXin,
LiLing Jesse
Publication year - 2009
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2009.03467.x
Subject(s) - verapamil , pharmacokinetics , genotype , p glycoprotein , pharmacology , medicine , pharmacogenetics , gene , biology , genetics , multiple drug resistance , antibiotics , calcium
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The pharmacokinetics of verapamil have been assessed in a number of studies. • As a substrate of P‐glycoprotein (P‐gp), verapamil shows a large inter‐individual variability in terms of plasma concentrations. • It has been confirmed that polymorphisms of the ABCB1 gene at positions 2677 and 3435 are related to the expression and function of P‐gp. WHAT THIS STUDY ADDS • This study has confirmed that polymorphisms of ABCB1 gene may influence the pharmacokinetics of verapamil among healthy Chinese Han ethnic subjects. AIMS To assess the association between polymorphisms of the ABCB1 gene and the pharmacokinetics of verapamil among healthy Chinese Han ethnic subjects. METHODS Based on polymorphisms of the ABCB1 gene at positions 2677 and 3435, 24 healthy male participants were divided into three groups: 2677GG/3435CC ( n = 6), 2677GT/3435CT ( n = 12) and 2677TT/3435TT ( n = 6). Each subject had received a single oral dose of verapamil (80 mg) under fasting conditions. Multiple blood samples were collected over 24 h, and plasma concentrations of verapamil were determined by HPLC. Pharmacokinetic characteristics were compared between the different genotypic groups. RESULTS The pharmacokinetics parameters of verapamil differed significantly among the three genotypic groups. AUC(last) was significantly lower among individuals with the 2677TT/3435TT (159.5 ± 79.0 ng ml −1 h) and 2677GT/3435CT (189.3 ± 73.1 ng ml −1 h) genotypes than those with the 2677GG/3435CC genotype (303.1 ± 83.7 ng ml −1 h) ( P = 0.004 and P = 0.008, respectively). However, the CL/ F value was higher among subjects with the 2677TT/3435TT (523.0 ± 173.7 l h −1 ) genotype than those with the 2677GT/3435CT (452.2 ± 188.6 l h −1 ) or 2677GG/3435CC (265.4 ± 72.8 l h −1 ) genotypes. A significant difference was also found between the latter two groups ( P = 0.034). In addition, the C max tended to be higher among subjects with the 2677GG/3435CC genotype than those with the 2677GT/3435CT or 2677TT/3435TT genotypes (42.2 ± 3.9 vs 32.2 ± 16.2 vs 38.1 ± 13.7 ng ml −1 ). CONCLUSIONS Our study showed for the first time that verapamil pharmacokinetics may be influenced by particular genetic polymorphisms of the ABCB1 gene among healthy Chinese Han ethnic subjects. An individualized dosage regimen design incorporating such information may improve the efficacy of the drug whilst reducing adverse reactions.