Inhibitory effect of erythromycin P-glycoprotein-mediated biliary excretion of doxorubicin in rats

S. I. Kiso, Hui Cai Shao Hui Cai, K. Kitaichi, N. Furui, K. Takagi, K. Takagi, T. Nabeshima, T. Hasegawa

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33 Citations (Scopus)


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 μM) from P388/ADR cells in a concentration-dependent manner. In rats receiving constant-rate infusion of doxorubicin (30 μg/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 V(max)/K(m), K(m) and K(i) were 8.79 ml/minute, 0.82 μg/ml and 0.41 μg/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.

Original languageEnglish
Pages (from-to)2827-2834
Number of pages8
JournalAnticancer research
Issue number5
Publication statusPublished - 09-11-2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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