OII-B-1The role of NA+-taurocholate cotransporting polypeptide (NTCP) in the hepatic uptake of rosuvastatin

Abstract

BACKGROUND Rosuvastatin is an HMG-CoA reductase inhibitor (statin) used in the treatment of dyslipidemia. Rosuvastatin is not subject to significant metabolism and we have previously shown a role of OATP transporters for rosuvastatin uptake. AIM We assessed the extent and relevance of bile acid uptake transporters to rosuvastatin uptake. METHOD The hepatic bile acid uptake transporter NTCP and the intestinal bile acid uptake transporter apical sodium-dependent bile acid transporter (ASBT) were expressed in HeLa cells utilizing a recombinant vaccinia system. Allelic variants of human NTCP were also assessed. NTCP expression relative to OATP mRNA was determined from a bank of human liver samples. RESULT We demonstrate the major human hepatic bile acid uptake transporter NTCP, but not rat Ntcp or ASBT, can transport rosuvastatin. Human hepatocyte studies suggest NTCP accounts for nearly 50% of rosuvastatin uptake. Remarkably, NTCP*2 (C800T; S267F), a variant associated with near complete loss of function for bile acid uptake, exhibited a profound gain of function for rosuvastatin uptake. Quantitative mRNA analysis revealed marked intersubject variability in expression of OATPs and NTCP. CONCLUSION NTCP may be a heretofore unrecognized transporter important to the hepatic uptake of rosuvastatin and possibly other drugs/statins in clinical use. Accordingly, expression and polymorphisms in NTCP may be an additional determinant of intersubject variability in response to statin therapy. Clinical Pharmacology & Therapeutics (2005) 79, P5–P5; doi: 10.1016/j.clpt.2005.12.014