MolPharm xPharm- The Comprehensive Pharmacology Reference

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on February 1, 2008; DOI: 10.1124/mol.107.041459

0026-895X/08/7305-1474-1483$20.00
Mol Pharmacol 73:1474-1483, 2008

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.107.041459v1
73/5/1474    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Matsushima, S.
Right arrow Articles by Sugiyama, Y.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Matsushima, S.
Right arrow Articles by Sugiyama, Y.

Involvement of Multiple Efflux Transporters in Hepatic Disposition of Fexofenadine

Soichiro Matsushima, Kazuya Maeda, Hisamitsu Hayashi, Yasuyuki Debori, Alfred H. Schinkel, John D. Schuetz, Hiroyuki Kusuhara, and Yuichi Sugiyama

Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan. (S.M., K.M., H.H., Y.D., H.K., Y.S.); Division of Experimental Therapy, the Netherlands Cancer Institute, Amsterdam, the Netherlands (A.H.S.); and Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (J.D.S.)

Fexofenadine (FEX) is mainly eliminated from the liver into bile in unchanged form. We demonstrated previously that organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are involved in the hepatic uptake of FEX. However, little is known about the mechanisms controlling the hepatic efflux of FEX from the liver to bile and blood. In the present study, the involvement of hepatic efflux transporters in the pharmacokinetics of FEX was investigated in both in vitro and in vivo studies. Vectorial transport of FEX was observed in OATP1B3/human bile salt export pump (hBSEP) double transfectants but not in OATP1B3/human breast cancer resistance protein double transfectants, which indicates the possible contribution of hBSEP to the biliary excretion of FEX in humans. In multidrug resistance-associated protein 2 (Mrp2)-/- mice, the biliary excretion clearance based on the plasma concentration and the liver-to-plasma concentration ratio significantly decreased, whereas the biliary excretion clearance based on the liver concentration decreased only with 20%, suggesting the minimum contribution of Mrp2 to its biliary excretion. ATP-dependent transport of FEX was observed in hMRP3-enriched membrane vesicles but not hMRP4. In Mrp3-/- mice, the biliary excretion clearance based on both the plasma and liver concentration and the liver-to-plasma concentration ratio increased, suggesting the significant contribution of Mrp3 to its sinusoidal efflux and the up-regulation of its biliary excretion in Mrp3-/- mice. On the other hand, pharmacokinetics of FEX remained unchanged in Mrp4-/- mice. This information provides a novel insight into the transporters important for FEX disposition.

Received September 3, 2007; accepted February 1, 2008

Address correspondence to: Dr. Yuichi Sugiyama, Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2008 by the American Society for Pharmacology and Experimental Therapeutics