Erythromycin Effects on Multiple-Dose Carbamazepine Kinetics

To determine the effects of erythromycin on multiple-dose carbamazepine pharmacokinetics, seven healthy male volunteers were given 300-400 mg of carbamazepine each morning for 17 consecutive days. All subjects were given a placebo erythromycin form every 6 h on days 12, 13, and 14, then changed to erythromycin base 250 mg every 6 h for the final 3 days. Serial blood samples were drawn after the morning doses on days 14 and 17. Analysis of carbamazepine and carbamazepine-10,11-epoxide concentrations were made by high-performance liquid chromatography. Pharmacokinetic analysis showed carbamazepine half-life and 24-h postdose concentration to increase significantly (p less than 0.05) and oral clearance to decrease (p less than 0.05) during erythromycin administration. Decreases in carbamazepine-10,11-epoxide Cmax (p less than 0.001), area under the concentration-time curve0-24 (p less than 0.001), and carbamazepine-10,11-epoxide to carbamazepine ratio (p less than 0.01) also occurred during carbamazepine dosing. Erythromycin significantly inhibits the epoxide-diol metabolic pathway by which carbamazepine is transformed to carbamazepine-10,11-epoxide. Wide individual variability in this interaction should serve to warn practitioners of the unpredictability of this interaction.