Mixed effects of OATP1B1, BCRP and NTCP polymorphisms on the population pharmacokinetics of pravastatin in healthy volunteers

作者：Lu, Xue-Feng; Zhou, Yang; Bi, Kai-Shun; Chen, Xiao-Hui^*

来源：Xenobiotica, 2016, 46(9): 841-849.

DOI：10.3109/00498254.2015.1130881

• BCRP
• genetic polymorphisms
• NTCP
• OATP1B1
• population pharmacokinetics
• pravastatin

1.Pravastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used for the treatment of hyperlipidaemia. This study aims to investigate the effects of genetic polymorphisms in OATP1B1, BCRP and NTCP on pravastatin population pharmacokinetics in healthy Chinese volunteers using a non-linear mixed-effect modelling (NONMEM) approach. A two-compartment model with a first-order absorption and elimination described plasma pravastatin concentrations well.2.Genetic polymorphisms of rs4149056 (OATP1B1) and rs2306283 (OATP1B1) were found to be associated with a significant (p<0.01) decrease in the apparent clearance from the central compartment (CL/F), while rs2296651 (NTCP) increased CL/F to a significant degree (p<0.01). The combination of these three polymorphisms reduced the inter-individual variability of CL/F by 78.8%.3.There was minimal effect of rs2231137 (BCRP) and rs2231142 (BCRP) on pravastatin pharmacokinetics (0.010.05).4.The current data suggest that the combination of rs4149056, rs2306283 and rs2296651 polymorphisms is an important determinant of pravastatin pharmacokinetics.

• 出版日期2016-9
• 单位辽宁大学; 沈阳药科大学