Drug and Bile Acid Transporters in Rosuvastatin Hepatic Uptake: Function, Expression, and Pharmacogenetics

Background & Aims The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, target liver HMG-CoA and are of proven benefit in the prevention of coronary heart disease. Rosuvastatin is an effective statin notable for liver selectivity and lack of significant metabolism. We assessed the extent and relevance of hepatic transporters to rosuvastatin uptake. Methods Transporters involved in rosuvastatin uptake were determined through heterologous expression of multiple human and rat uptake transporters. Human organic anion transporting polypeptide (OATP) 1B1 and sodium-dependent taurocholate cotransporting polypeptide (NTCP) allelic variants were also assessed. Expression of OATP and NTCP messenger RNA and protein was determined from a bank of human liver samples. Results Multiple OATP family members, including 1B1, 1B3, 2B1, and 1A2, were capable of rosuvastatin transport. Naturally occurring polymorphisms in OATP1B1, including *5, *9, *15, and *18, were associated with profound loss of activity toward rosuvastatin. Interestingly, the major human hepatic bile acid uptake transporter NTCP, but not rat Ntcp, also transported rosuvastatin. Human hepatocyte studies suggested that NTCP alone accounted for ∼35% of rosuvastatin uptake. Remarkably, NTCP*2, a variant known to have a near complete loss of function for bile acids, exhibited a profound gain of function for rosuvastatin. Quantitative messenger RNA analysis revealed marked intersubject variability in expression of OATPs and NTCP. Conclusions Multiple transporters mediate the overall hepatic uptake of rosuvastatin, and NTCP may be a heretofore unrecognized transporter important to the disposition of rosuvastatin and possibly other drugs/statins in clinical use. Accordingly, transporter expression and polymorphisms may be key determinants of intersubject variability in response to statin therapy in general.