SLCO1B1 521T-->C functional genetic polymorphism and lipid-lowering efficacy of multiple-dose pravastatin in Chinese coronary heart disease patients.
OBJECTIVE
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 alpha 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.
Zhang
Wei
W
Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China.
Chen
Bi-Lian
BL
Ozdemir
Vural
V
He
Yi-Jing
YJ
Zhou
Gan
G
Peng
Dao-Di
DD
Deng
Sheng
S
Xie
Qi-Ying
QY
Xie
Wei
W
Xu
Lin-Yong
LY
Wang
Lian-Ci
LC
Fan
Lan
L
Wang
An
A
Zhou
Hong-Hao
HH
D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D044466:Asian People; D002784:Cholesterol / Q000378:metabolism; D003327:Coronary Disease / Q000188:drug therapy*; D005260:Female; D005838:Genotype; D006801:Humans; D008055:Lipids / Q000097:blood*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D011110:Polymorphism, Genetic; D017035:Pravastatin / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D011446:Prospective Studies; D016896:Treatment Outcome
D000924:Anticholesteremic Agents; D008055:Lipids; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D002784:Cholesterol; D017035:Pravastatin