Drug-drug interaction between pitavastatin and various drugs via OATP1B1.
It has already been demonstrated that pitavastatin, a novel potent HMG-coenzyme A reductase inhibitor, is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP) 1B1. Because OATP2B1 is also localized in the basolateral membrane of human liver, we took two approaches to further confirm the minor contribution of OATP2B1 to the hepatic uptake of pitavastatin. Western blot analysis revealed that the ratio of the band density of OATP2B1 in human hepatocytes to that in our expression system is at least 6-fold lower compared with OATP1B1 and OATP1B3. The uptake of pitavastatin in human hepatocytes could be inhibited by both estrone-3-sulfate (OATP1B1/OATP2B1 inhibitor) and estradiol-17beta-D-glucuronide (OATP1B1/OATP1B3 inhibitor). These results further supported the idea that OATP1B1 is a predominant transporter for the hepatic uptake of pitavastatin. Then, to explore the possibility of OATP1B1-mediated drug-drug interaction, we checked the inhibitory effects of various drugs on the pitavastatin uptake in OATP1B1-expressing cells and evaluated whether the in vitro inhibition was clinically significant or not. As we previously reported, we used the methodology for estimating the maximum unbound concentration of inhibitors at the inlet to the liver (I(u,in,max)). Judging from I(u,in,max) and inhibition constant (K(i)) for OATP1B1, several drugs (especially cyclosporin A, rifampicin, rifamycin SV, clarithromycin, and indinavir) have potentials for interacting with OATP1B1-mediated uptake of pitavastatin. The in vitro experiments could support the clinically observed drug-drug interaction between pitavastatin and cyclosporin A. These results suggest that we should pay attention to the concomitant use of some drugs with pitavastatin.
Hirano
Masaru
M
Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, 113-0033 Japan.
Maeda
Kazuya
K
Shitara
Yoshihisa
Y
Sugiyama
Yuichi
Y
D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004347:Drug Interactions; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000378:metabolism*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D014162:Transfection
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011804:Quinolines; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C450859:SLCO2B1 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C025483:estradiol-17 beta-glucuronide; D004970:Estrone; D004958:Estradiol; D016572:Cyclosporine; C108475:pitavastatin; C017296:estrone sulfate