title: Inhibitory effect of erythromycin on P-glycoprotein-mediated biliary excretion of doxorubicin in rats.
abstract: The macrolide antibiotic erythromycin has recently been shown to overcome the resistance to anticancer drugs that results from overexpression of P-glycoprotein. The present study, using erythromycin lactobionic acid as a model drug, investigated the inhibitory effects of erythromycin on the efflux of doxorubicin from P388/ADR cells expressing P-glycoprotein and on the biliary excretion mechanism of doxorubicin in rats, which is primarily mediated by P-glycoprotein. Erythromycin lactobionic acid was found to inhibit the efflux of doxorubicin (5 microM) from P388/ADR cells in a concentration-dependent manner. In rats receiving constant-rate infusion of doxorubicin (30 micrograms/min), both the biliary and renal clearance of this drug dramatically decreased and its plasma concentrations increased after an intravenous injection of erythromycin lactobionic acid (100 mg/kg as erythromycin). These results suggest that erythromycin competitively inhibits P-glycoprotein-mediated biliary and renal excretion of doxorubicin. The effect of erythromycin on the biliary secretion of doxorubicin was also analyzed quantitatively by the competitive inhibition model. The computer-estimated values of Vmax/Km, Km and Ki were 8.79 ml/minute, 0.82 microgram/ml and 0.41 microgram/ml, respectively. The findings of these experiments suggest that the inhibitory effect of erythromycin on the P-glycoprotein-mediated biliary excretion of doxorubicin is competitive and that combination chemotherapy of doxorubicin with erythromycin may induce toxicity as a result of increased plasma concentrations of doxorubicin.
authors.affiliation: Department of Hospital Pharmacy, Nagoya University School of Medicine, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kiso
authors.forename: S H
authors.initials: SH
authors.lastname: Cai
authors.forename: K
authors.initials: K
authors.lastname: Kitaichi
authors.forename: N
authors.initials: N
authors.lastname: Furui
authors.forename: K
authors.initials: K
authors.lastname: Takagi
authors.forename: K
authors.initials: K
authors.lastname: Takagi
authors.forename: T
authors.initials: T
authors.lastname: Nabeshima
authors.forename: T
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism*; D004187:Disaccharides / Q000378:metabolism / Q000494:pharmacology; D004317:Doxorubicin / Q000378:metabolism* / Q000494:pharmacology; D004917:Erythromycin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology* / Q000652:urine; D007424:Intracellular Fluid / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D004187:Disaccharides; D004917:Erythromycin; C005608:lactobionic acid; D004317:Doxorubicin