The Influence of SLCO1B1 (OATP1B1) Gene Polymorphisms on Atorvastatin Blood Concentrations and related Side Effects

• Main Authors: Yi-Kai Wang, 王怡凱
• Other Authors: Yueh-Ching Chou
• Format: Others
• Language: zh-TW
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/90480795186829688913

碩士 === 國立陽明大學 === 藥理學研究所 === 100 === BACKGROUND: Statins are well established in the treatment of hypercholesterolaemia and the prevention of coronary artery disease. However, there is inter-individual variability in the response to statins, in terms of both lipid-lowering and adverse effects. The major action site of statins is hepatocytes and recent interest has focused on the genetic variation in hepatic influx and efflux transporters for their potential to explain these differences. Organic anion transporting polypeptides (OATP) is a family of influx transporters expressed in various tissues and occupies the important role for pharmacokinetics of statins. Among human OATP transporters expressed on the sinusoidal membrane of hepatocytes, OATP1B1 has been identified as substrates of statins. This study tries to explore whether genetic variability in genes encoding OATP transporters can result in inter-individual differences in serum concentration and adverse effects in patients in Taiwan. METHODS: Genotypes of SLCO1B1 exon 5, intron 5, exon 6 and intron 11 were analyzed in 72 patients, who received atorvastatin regularly. Serum atorvastatin concentrations were determined using high-performance liquid chromatographic methods. RESULTS: The calibration curves were linear over a concentration range of 5-300 ng/ml of atorvastatin with r2 of 0.999. The average recovery of the atorvastatin was 85%. The ratios of patients with the 388AA, 388AG and 388GG genotype were 4.2%, 23.6% and 72.2%, respectively. The ratios of patients with the 521TT, 521TC and 521CC genotype were 80.6%, 19.4% and 0%, respectively. ALT elevating was associated with concentrations of atorvastatin. However, there are no differences on atorvastatin related side effects and concentrations between SLCO1B1 genotyping groups. CONCLUSIONS: In this study, the incidence of 388A>G and 521T>C are 84% and 8.7%, respectively. There is considerably higher incidence of 388A>G in Taiwanese patients than that in Japanese (64%) and European-American (30%). The incidence of 521T>C (8.7%) is lower than Japanese (11%) and European-American (14%). However, the common variants in SLCO1B1 were not associated with an increased risk of atorvastatin-related side effects and concentrations of steady state of atorvastatin in Taiwanese population. The concentrations of atorvastatin were associated with an increased risk of atorvastatin related ALT elevating.