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

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, wing 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 muM) from P388/ADR cells in a concentration-dependent manner. In rats receiving constant-rate infusion of doxorubicin (30 mug/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 mug/ml and 0.41 mug/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.