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Acta Pharmacol Sin. 2019 Apr;40(4):492-499. doi: 10.1038/s41401-018-0013-y. Epub 2018 Jun 27.

Effects of SLCO1B1 and GATM gene variants on rosuvastatin-induced myopathy are unrelated to high plasma exposure of rosuvastatin and its metabolites.

Author information

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.
6
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510020, China. huangmin@mail.sysu.edu.cn.
7
Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China. zhongsl@hotmail.com.

Abstract

Myotoxicity is a significant factor contributing to the poor adherence and reduced effectiveness in the treatment of statins. Genetic 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 N-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-performance 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 (Padj < 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% CI: 1.180-2.568, P = 0.0052, FDR = 0.0468). Glycine amidinotransferase (GATM) rs9806699 was marginally associated with SIM incidents (OR: 0.617, 95% CI: 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.

KEYWORDS:

genetic polymorphism; metabolites; myopathy; plasma concentration; rosuvastatin

PMID:
29950617
PMCID:
PMC6461793
[Available on 2020-04-01]
DOI:
10.1038/s41401-018-0013-y
[Indexed for MEDLINE]

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