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

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, 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, cefotetan, 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.

• Authors: Yukio Kato, Seiko Takahara, Sayaka Kato, Yoshiyuki Kubo, Yoshimichi Sai, Ikumi Tamai, Hikaru Yabuuchi, Akira Tsuji
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 36 Issue 6 Pg. 1088-96 (Jun 2008) ISSN: 1521-009X [Electronic] United States
• PMID: 18339814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCC2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Abcc2 protein, rat
• Abcg2 protein, rat
• Anti-Bacterial Agents
• Cephalosporins
• Multidrug Resistance-Associated Protein 2

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Animals
• Animals, Genetically Modified
• Anti-Bacterial Agents (blood, metabolism, pharmacokinetics)
• Bile (metabolism)
• Cell Membrane Permeability
• Cephalosporins (blood, metabolism, pharmacokinetics)
• Humans
• Hyperbilirubinemia (metabolism)
• Kidney (metabolism)
• Liver (metabolism)
• Male
• Molecular Weight
• Multidrug Resistance-Associated Protein 2
• Rats
• Rats, Sprague-Dawley