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

Anticancer Res. Sep-Oct 2000;20(5A):2827-34.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Anti-Bacterial Agents / blood
  • Anti-Bacterial Agents / metabolism*
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / urine
  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / pharmacology
  • Biliary Tract / drug effects
  • Biliary Tract / metabolism*
  • Disaccharides / metabolism
  • Disaccharides / pharmacology
  • Doxorubicin / metabolism*
  • Doxorubicin / pharmacology
  • Erythromycin / blood
  • Erythromycin / metabolism
  • Erythromycin / pharmacology*
  • Erythromycin / urine
  • Intracellular Fluid / metabolism
  • Kidney / metabolism
  • Male
  • Mice
  • Rats
  • Rats, Wistar
  • Tumor Cells, Cultured


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-Bacterial Agents
  • Antineoplastic Agents
  • Disaccharides
  • Erythromycin
  • lactobionic acid
  • Doxorubicin