title: Involvement of the drug transporters p glycoprotein and multidrug resistance-associated protein Mrp2 in telithromycin transport.
abstract: 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.
authors.affiliation: Department of Medical Technology, Nagoya University School of Health Sciences, Daikominami, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Ying Lan
authors.initials: YL
authors.lastname: Zhao
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nadai
authors.forename: Hideo
authors.initials: H
authors.lastname: Yoshizumi
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Cen
authors.forename: Shoko
authors.initials: S
authors.lastname: Torita
authors.forename: Kenji
authors.initials: K
authors.lastname: Takagi
authors.forename: Kenzo
authors.initials: K
authors.lastname: Takagi
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D048628:Ketolides / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D048628:Ketolides; D026901:Membrane Transport Proteins; D004317:Doxorubicin; C106791:telithromycin