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

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 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
Volume20
Issue number5
Publication statusPublished - 09-11-2000
Externally publishedYes

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P-Glycoprotein
Erythromycin
Doxorubicin
Hepatobiliary Elimination
Pharmaceutical Preparations
Macrolides
Combination Drug Therapy
Intravenous Injections
Anti-Bacterial Agents
Kidney

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kiso, S. I., Shao Hui Cai, H. C., Kitaichi, K., Furui, N., Takagi, K., Takagi, K., ... Hasegawa, T. (2000). Inhibitory effect of erythromycin P-glycoprotein-mediated biliary excretion of doxorubicin in rats. Anticancer research, 20(5), 2827-2834.
Kiso, S. I. ; Shao Hui Cai, Hui Cai ; Kitaichi, K. ; Furui, N. ; Takagi, K. ; Takagi, K. ; Nabeshima, T. ; Hasegawa, T. / Inhibitory effect of erythromycin P-glycoprotein-mediated biliary excretion of doxorubicin in rats. In: Anticancer research. 2000 ; Vol. 20, No. 5. pp. 2827-2834.
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Kiso, SI, Shao Hui Cai, HC, Kitaichi, K, Furui, N, Takagi, K, Takagi, K, Nabeshima, T & Hasegawa, T 2000, 'Inhibitory effect of erythromycin P-glycoprotein-mediated biliary excretion of doxorubicin in rats', Anticancer research, vol. 20, no. 5, pp. 2827-2834.

Inhibitory effect of erythromycin P-glycoprotein-mediated biliary excretion of doxorubicin in rats. / Kiso, S. I.; Shao Hui Cai, Hui Cai; Kitaichi, K.; Furui, N.; Takagi, K.; Takagi, K.; Nabeshima, T.; Hasegawa, T.

In: Anticancer research, Vol. 20, No. 5, 09.11.2000, p. 2827-2834.

Research output: Contribution to journalArticle

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AU - Kiso, S. I.

AU - Shao Hui Cai, Hui Cai

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AU - Furui, N.

AU - Takagi, K.

AU - Takagi, K.

AU - Nabeshima, T.

AU - Hasegawa, T.

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Kiso SI, Shao Hui Cai HC, Kitaichi K, Furui N, Takagi K, Takagi K et al. Inhibitory effect of erythromycin P-glycoprotein-mediated biliary excretion of doxorubicin in rats. Anticancer research. 2000 Nov 9;20(5):2827-2834.