Effects of SLCO1 Bl and GATM gene variants on rosuvastatin-induced myopathy are unrelated to high plasma exposure of rosuvastatin and its metabolites  

作　　者：Xue Bai Bin Zhang Ping Wang Guan-lei Wang Jia-li Li Ding-sheng Wen Xing-zhen Long Hong-shuo Sun Yi-bin Liu Min Huang Shi-Iong Zhong 

机构地区：[1]Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510020, China [2]Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China [3]Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China [4]Guizhou Province Hospital of Traditional Chinese Medicine, Guiyang 550001, China [5]Departments of Surgery, Physiology and Pharmacology, Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada

出　　处：《Acta Pharmacologica Sinica》2019年第4期492-499,共8页中国药理学报（英文版）

基　　金：National Key R&D Program (No. 2017YFC0909301, 2017YFC0909302, 2017YFC0909303, 2016YFC0905003);the National Natural Science Foundation of China (No. 81673514, 81373486);the Science and Technology Development Projects of Guangdong Province, China (No. 2016B090918114);the Science and Technology Development Projects of Guangzhou, Guangdong, China (201510010236, 201604020096).

摘　　要：Myotoxicity is a sign ificant factor contributi ng to the poor adhere nee and reduced effective ness in the treatme nt of statins. Gen etic variations and high drug plasma exposure are considered as critique causes for statin-induced myopathy (SIM). This study aims to explore the sequential influences of rosuvastatin (RST) pharmacokinetic and myopathy-related single-nucleotide polymorphisms (SNPs) on the plasma exposure to RST and its metabolites: rosuvastatin lactone (RSTL) and /V-desmethyl rosuvastatin (DM-RST), and further on RST-induced myopathy. A total of 758 Chinese patients with coronary artery disease were enrolled and followed up SIM incidents for 2 years. The plasma concentrations of RST and its metabolites were determined through a validated ultra-performanee liquid chromatography mass spectrometry method. Nine SNPs in six genes were genotyped by using the Sequenom MassArray iPlex platform. Results revealed that ABCG2 rs2231142 variations were highly associated with the plasma concentrations of RST, RSTL, and DM-RST (Pad)<0.01, FDR < 0.05). CYP2C9 rs1057910 significantly affected the DM-RST concentration (Padj <0.01, FDR < 0.05). SLCO1B1 rs4149056 variant allele was significantly associated with high SIM risk (OR: 1.741, 95% Cl: 1.180-2.568, P = 0.0052, FDR = 0.0468). Glycine amidinotransferase (GATM) rs9806699 was marginally associated with SIM incidents (OR: 0.617, 95% Cl: 0.406-0.939, P = 0.0240, FDR = 0.0960). The plasma concentrations of RST and its metabolites were not significantly different between the SIM (n = 51) and control groups (n=707)(all P > 0.05). In conclusion, SLCO1B1 and GATM genetic variants are potential biomarkers for predicting RST-induced myopathy, and their effects on SIM are unrelated to the high plasma exposure of RST and its metabolites.

关 键 词：genetic POLYMORPHISM ROSUVASTATIN METABOLITES PLASMA concentration MYOPATHY 

分 类 号：R[医药卫生]