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Drug Metabolism and Disposition Fast Forward
First published on March 13, 2008; DOI: 10.1124/dmd.107.019125

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Received for publication November 13, 2007.
Revised February 10, 2008.
Accepted for publication March 12, 2008.

Involvement of multidrug resistance-associated protein 2 (Abcc2) in molecular weight-dependent biliary excretion of {beta}-lactam antibiotics

Yukio Kato 1, Seiko Takahara 1, Sayaka Kato 1, Yoshiyuki Kubo 1, Yoshimichi Sai 1, Ikumi Tamai 1, Hikaru Yabuuchi 2, Akira Tsuji 1*

1 Graduate School of Natural Science and Technology, Kanazawa University 2 GenoMembrane Inc.

* Address correspondence to: E-mail: tsuji{at}kenroku.kanazawa-u.ac.jp

Abstract

In the present study, we attempted to identify the membrane permeation process(es) primarily involved in the molecular-weight-dependent biliary excretion of {beta}-lactam antibiotics. A search of the literature indicated that the molecular weight threshold operates mainly in the transport process across bile canalicular membranes. We confirmed that biliary clearance of the model biliary-excretion-type cephalosporin cefoperazone was reduced to 10% of the control in Eisai hyperbilirubinemic rats (EHBRs), which are genetically deficient in multidrug resistance-associated protein (Mrp) 2, indicating that Mrp2 plays a major role as an efflux transporter on the canalicular membranes. ATP-dependent uptake of several cephalosporins including cefoperazone, cefbuperazone, cefpiramide and ceftriaxone, all of which are mainly excreted into bile, was confirmed in membrane vesicles from Sf9 cells transfected with rat Mrp2. Both the inhibitory potency of the cephalosporins for Mrp2-mediated transport and the uptake of cephalosporins by Mrp2-expressing vesicles were molecular-weight-dependent, suggesting that Mrp2 is one of the major transporters involved in molecular-weight-dependent biliary excretion. An uptake study in membrane vesicles of Sf9 cells transfected with breast cancer resistance protein (Bcrp) revealed that Bcrp accepts cefoperazone, cefbuperazone, cefpiramide, cefotetane, ceftriaxone, cefotiam, cefamandole and cefazolin as substrates, and Bcrp-mediated transport was also molecular weight-dependent, suggesting that Bcrp also contributes to molecular-weight-dependent biliary excretion of {beta}-lactam antibiotics in rats.


Key words: ABC transporters, antibiotics, biliary excretion, drug efflux, drug secretion, hepatic transport, hepatobiliary transport, MRP, pharmacokinetics, transporters


This article has been cited by other articles:


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 Drug Metab. Dispos.Home page
H. Fukuda, R. Ohashi, M. Tsuda-Tsukimoto, and I. Tamai
Effect of Plasma Protein Binding on in Vitro-in Vivo Correlation of Biliary Excretion of Drugs Evaluated by Sandwich-Cultured Rat Hepatocytes
Drug Metab. Dispos., July 1, 2008; 36(7): 1275 - 1282.
[Abstract] [Full Text] [PDF]


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