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Antimicrobial Agents and Chemotherapy, January 2006, p. 80-87, Vol. 50, No. 1
0066-4804/06/$08.00+0 doi:10.1128/AAC.50.1.80-87.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Involvement of the Drug Transporters P Glycoprotein and Multidrug Resistance-Associated Protein Mrp2 in Telithromycin Transport
Shoji Yamaguchi,1,
Ying Lan Zhao,2,3,
Masayuki Nadai,4
Hideo Yoshizumi,4
Xiaobo Cen,3
Shoko Torita,1
Kenji Takagi,1
Kenzo Takagi,1 and
Takaaki Hasegawa2*
Department of Medical Technology, Nagoya University School of Health Sciences, Daikominami, Higashi-ku, Nagoya 461-8673,1 Department of Pharmacy and Pharmacokinetics, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195,2 Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku, Nagoya 468-8503, Japan,4 National Chengdu Center for Safety Evaluation of Traditional Chinese Medicine, West China Hospital, Sichuan University, Chengdu 610041, China3
Received 7 June 2005/ Returned for modification 7 July 2005/ Accepted 29 October 2005
The present study aims to investigate the role of P glycoprotein and multidrug resistance-associated protein (Mrp2) in the transport of telithromycin, a newly developed ketolide antibiotic, in vitro and in vivo. The in vitro experiments revealed that the intracellular accumulation of telithromycin in adriamycin-resistant human chronic myelogenous leukemia cells (K562/ADR) overexpressing P glycoprotein was significantly lower than that in human chronic myelogenous leukemia cells (K562/S) not expressing P glycoprotein. Cyclosporine significantly increased the intracellular accumulation of telithromycin in K562/ADR cells. When telithromycin was coadministered intravenously with cyclosporine in Sprague-Dawley (SD) rats, cyclosporine significantly delayed the disappearance of telithromycin from plasma and decreased its systemic clearance to 60% of the corresponding control values. Hepatobiliary excretion experiments revealed that cyclosporine almost completely inhibited the biliary clearance of telithromycin, suggesting that telithromycin is a substrate of P glycoprotein and a potential substrate of Mrp2. Moreover, the biliary clearance of telithromycin was significantly decreased by 80% in Eisai hyperbilirubinemic mutant rats with a hereditary deficiency in Mrp2, indicating that Mrp2, as well as P glycoprotein, plays an important role in the biliary excretion of telithromycin. When the effect of telithromycin on the biliary excretion of doxorubicin, a substrate of P glycoprotein and Mrp2, was examined in SD rats, telithromycin significantly decreased the biliary clearance of doxorubicin by 80%. Results obtained from this study indicate that telithromycin is a substrate of both P glycoprotein and Mrp2, and these transporters are involved in the hepatobiliary transport of telithromycin.
* Corresponding author. Mailing address: Department of Pharmacy and Pharmacokinetics, Aichi Medical University School of Medicine, Nagakute-cho, Aichi-gun, Aichi 480-1195, Japan. Phone: 81-561-63-1011. Fax: 81-561-63-1028. E-mail: takahase{at}aichi-med-u.ac.jp.
S.Y. and Y.L.Z. contributed equally to this work.
Antimicrobial Agents and Chemotherapy, January 2006, p. 80-87, Vol. 50, No. 1
0066-4804/06/$08.00+0 doi:10.1128/AAC.50.1.80-87.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
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