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SLCO1B1 521T→C functional genetic polymorphism and lipid‐lowering efficacy of multiple‐dose pravastatin in Chinese coronary heart disease patients
Author(s) -
Zhang Wei,
Chen BiLian,
Ozdemir Vural,
He YiJing,
Zhou Gan,
Peng DaoDi,
Deng Sheng,
Xie QiYing,
Xie Wei,
Xu LinYong,
Wang LianCi,
Fan Lan,
Wang An,
Zhou HongHao
Publication year - 2007
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.1365-2125.2007.02892.x
Subject(s) - pravastatin , slco1b1 , medicine , pharmacology , reductase , hmg coa reductase , cholesterol , biology , pharmacogenetics , biochemistry , enzyme , gene , genotype
What is already known about this subject • Both oral clearance as well as delivery of pravastatin to its molecular targets in hepatoctyes are greatly influenced by the organic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1. • The role of genetic factors that determine the marked interindividual variability in lipid‐lowering efficacy of pravastatin in Chinese patients is not known. • The present study was designed to evaluate the impact of a common functional genetic polymorphism in SLCO1B1 (521T→C: Val174Ala) on pravastatin efficacy in Chinese patients with coronary heart disease. What this study adds 521T→C functional genetic polymorphism of SLCO1B1 is significantly associated with an attenuated total cholesterol‐lowering efficacy of pravastatin in Chinese patients with coronary heart disease. Aims Pravastatin is a 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor, which is widely used both in primary and secondary prevention of coronary heart disease (CHD). Pravastatin is not subject to metabolism by cytochrome P450s, but it is actively transported from blood into target tissues (e.g. hepatocytes in the liver) by the organic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1. The aim of the present study was to evaluate the impact of SLCO1B1 521T→C (Val174Ala) functional genetic polymorphism on the lipid‐lowering efficacy of multiple‐dose pravastatin in Chinese patients with CHD. Methods Forty‐five hospitalized patients with CHD prospectively received pravastatin as a single‐agent therapy (20 mg day −1 p.o.) for 30 days. Serum triglycerides, total cholesterol, low‐density lipoprotein‐cholesterol and high‐density lipoprotein‐cholesterol concentrations were determined before and after pravastatin treatment. Results Pravastatin treatment significantly decreased plasma lipids in all patients ( P < 0.001). Importantly, we showed an attenuated pravastatin pharmacodynamic effect on total cholesterol in patients with 521TC heterozygote genotype (from 5.52 ± 0.51 mmol l −1 to 4.70 ± 0.35 mmol l −1 , % change −14.5 ± 6.6%, N = 9) compared with 521TT homozygote genotype (from 5.47 ± 1.15 mmol l −1 to 4.21 ± 0.89 mmol l −1 , % change −22.4 ± 10.3%, N = 36) (mean ± SD, P = 0.03, two‐tailed test with α set at 5%). SLCO1B1 521T→C functional polymorphism did not significantly influence pravastatin pharmacodynamics on other plasma lipids ( P > 0.05). Conclusions The 521T→C polymorphism of SLCO1B1 appears to modulate significantly the total cholesterol‐lowering efficacy of pravastatin in Chinese patients with CHD. Further studies are warranted to determine the extent to which SLCO1B1 genetic variation may contribute to resistance to pravastatin in Asian patients treated with standard doses of pravastatin.