![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (M.H., K.M., Y.Su.); and Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Sh.)
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-17ß-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 (Iu,in,max). Judging from Iu,in,max and inhibition constant (Ki) 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.
This article has been cited by other articles:
|
|
 |
|
  A. Poirier, T. Lave, R. Portmann, M.-E. Brun, F. Senner, M. Kansy, H.-P. Grimm, and C. Funk Design, Data Analysis, and Simulation of in Vitro Drug Transport Kinetic Experiments Using a Mechanistic in Vitro Model Drug Metab. Dispos., December 1, 2008; 36(12): 2434 - 2444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kitamura, K. Maeda, Y. Wang, and Y. Sugiyama Involvement of Multiple Transporters in the Hepatobiliary Transport of Rosuvastatin Drug Metab. Dispos., October 1, 2008; 36(10): 2014 - 2023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Kilford, M. Gertz, J. B. Houston, and A. Galetin Hepatocellular Binding of Drugs: Correction for Unbound Fraction in Hepatocyte Incubations Using Microsomal Binding or Drug Lipophilicity Data Drug Metab. Dispos., July 1, 2008; 36(7): 1194 - 1197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-i. Umehara, M. Iwai, Y. Adachi, T. Iwatsubo, T. Usui, and H. Kamimura Hepatic Uptake and Excretion of (-)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a Novel If Channel Inhibitor, in Rats and Humans Drug Metab. Dispos., June 1, 2008; 36(6): 1030 - 1038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Matsushima, K. Maeda, N. Ishiguro, T. Igarashi, and Y. Sugiyama Investigation of the Inhibitory Effects of Various Drugs on the Hepatic Uptake of Fexofenadine in Humans Drug Metab. Dispos., April 1, 2008; 36(4): 663 - 669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ishiguro, K. Maeda, A. Saito, W. Kishimoto, S. Matsushima, T. Ebner, W. Roth, T. Igarashi, and Y. Sugiyama Establishment of a Set of Double Transfectants Coexpressing Organic Anion Transporting Polypeptide 1B3 and Hepatic Efflux Transporters for the Characterization of the Hepatobiliary Transport of Telmisartan Acylglucuronide Drug Metab. Dispos., April 1, 2008; 36(4): 796 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Noe, R. Portmann, M.-E. Brun, and C. Funk Substrate-Dependent Drug-Drug Interactions between Gemfibrozil, Fluvastatin and Other Organic Anion-Transporting Peptide (OATP) Substrates on OATP1B1, OATP2B1, and OATP1B3 Drug Metab. Dispos., August 1, 2007; 35(8): 1308 - 1314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Treiber, R. Schneiter, S. Hausler, and B. Stieger Bosentan Is a Substrate of Human OATP1B1 and OATP1B3: Inhibition of Hepatic Uptake as the Common Mechanism of Its Interactions with Cyclosporin A, Rifampicin, and Sildenafil Drug Metab. Dispos., August 1, 2007; 35(8): 1400 - 1407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Seithel, S. Eberl, K. Singer, D. Auge, G. Heinkele, N. B. Wolf, F. Dorje, M. F. Fromm, and J. Konig The Influence of Macrolide Antibiotics on the Uptake of Organic Anions and Drugs Mediated by OATP1B1 and OATP1B3 Drug Metab. Dispos., May 1, 2007; 35(5): 779 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ishiguro, K. Maeda, W. Kishimoto, A. Saito, A. Harada, T. Ebner, W. Roth, T. Igarashi, and Y. Sugiyama PREDOMINANT CONTRIBUTION OF OATP1B3 TO THE HEPATIC UPTAKE OF TELMISARTAN, AN ANGIOTENSIN II RECEPTOR ANTAGONIST, IN HUMANS Drug Metab. Dispos., July 1, 2006; 34(7): 1109 - 1115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Yamashiro, K. Maeda, M. Hirouchi, Y. Adachi, Z. Hu, and Y. Sugiyama INVOLVEMENT OF TRANSPORTERS IN THE HEPATIC UPTAKE AND BILIARY EXCRETION OF VALSARTAN, A SELECTIVE ANTAGONIST OF THE ANGIOTENSIN II AT1-RECEPTOR, IN HUMANS Drug Metab. Dispos., July 1, 2006; 34(7): 1247 - 1254. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
