Influence of genetic polymorphisms in drug metabolism enzymes and transporters on pharmacokinetics of different fluvastatin formulations  

作　　者：Qian XIANG Jun-yu XU Ling-yue MA Nan ZHAO Xiao-dan ZHANG Qiu-fen XIE Zhuo ZHANG Xia ZHAO Yi-min CUI 

机构地区：[1]Department of Pharmacy, Peking University First Hospital, Beijing 100034, China

出　　处：《中国药理学与毒理学杂志》2018年第4期317-317,共1页Chinese Journal of Pharmacology and Toxicology

摘　　要：OBJECTIVE The purpose of the present study was to investigate the impact of fluvas.tatin formulation on the pharmacokinetics-genetic polymorphis relationship.METHODS We compared the difference between the pharmacokinetics of fluvastatin as an extended-release(ER) 80 mg tablet and an immediate-release(IR) 40 mg capsule in terms of drug metabolism enzyme and transporter ge.netic polymorphisms.In this open-label,randomized,two-period,two-treatment,crossover study,ef.fects of BCRP,SLCO1B1,MDR1,CYP2C9,and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed in 24 healthy individuals.Each treatment duration was 7 days with a washout period of 7 days between the crossover.Serum concentration of fluvastatin was evaluated using highperformance liquid chromatography-tandem mass spectrometry.RESULTS The SLCO1 B1 T521 C genotype had no statistically significant effect on IR 40 mg capsule of fluvastatinafter single or repeated doses.However,for the ER 80 mg tablet,the SLCO1 B1 T521 C genotype correlated with the AUC_(0-24) of repeat doses(P=0.01).The CYP2C9*3 genotype correlated with the AUC_(0-24) after the first dose IR40 mg capsule(P<0.05);however,the difference between CYP2C9*1/*1 and CYP2 C9*1/*3 was not statistically significant after repeated doses.CONCLUSION The effect of SLCO1B1T521C on fluvas.tatin exposure was observed and was more profound in ER and repeated dose administration than in IR and single dose administration.We recommend that formulation should be incorporated into future pharmacogenomics studies and clinical implication guidelines.OBJECTIVE The purpose of the present study was to investigate the impact of fluvastatin formulation on the pharmacokinetics-genetic polymorphis relationship. METHODS We compared the difference between the pharmacokinetics of fluvastatin as an extended-release （ER） 80 mg tablet and an immediate-release （IR） 40 mg capsule in terms of drug metabolism enzyme and transporter genetic polymorphisms. In this open-label, randomized, two-period, two-treatment, crossover study, effects of BCRP, SLCO1B1, MDR1, CYP2C9, and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed in 24 healthy individuals. Each treatment duration was 7 days with a washout period of 7 days between the crossover. Serum concentration of fluvastatin was evaluated using highperformance liquid chromatography-tandem mass spectrometry. RESULTS The SLCO1B1 T521C genotype had no statistically significant effect on IR 40 mg capsule of fluvastatinafter single or repeated doses. However, for the ER 80 mg tablet, the SLCO1B1 T521C genotype correlated with the AUC0-24 of repeat doses （P=0.01）. The CYP2C9＊3 genotype correlated with the AUC0-24 after the first dose IR 40 mg capsule （P〈0.05）; however, the difference between CYP2C9＊1/＊1 and CYP2C9＊1/＊3 was not statistically significant after repeated doses. CONCLUSION The effect of SLCO1B1 T521C on fluvastatin exposure was observed and was more profound in ER and repeated dose administration than in IR and single dose administration.We recommend that formulation should be incorporated into future pharmacogenomics studies and clinical implication guidelines.

关 键 词：氟伐他汀制剂 药物动力学 遗传学 临床分析 

分 类 号：R969.1[医药卫生—药理学] R394[医药卫生—药学]