The assumed metabolic breakdown of albendazole by mucosal CYP3A4 enzymes was studied by coadministering albendazole (10 mg/kg) with grapefruit juice. Concentrations of albendazole sulfoxide (ABZSX), the active metabolite of albendazole, were compared with those after albendazole was administered with water, a fatty meal, or grapefruit juice plus cimetidine (10 mg/kg). In comparison to water, maximum ABZSX concentration (Cmax) was enhanced 6.5-fold by a fatty meal (from 0.24 +/- 0.09 mg/l to 1.55 +/- 0.30 mg/l; mean +/- SD; P < 0.001) and 3.2-fold by grapefruit juice (from 0.24 +/- 0.09 mg/l to 0.76 +/- 0.37 mg/L; P = 0.031). When grapefruit juice was combined with cimetidine, Cmax was significantly lower than with grapefruit juice alone (0.41 +/- 0.29 mg/l and 0.76 +/- 0.37 mg/l, respectively; P = 0.022). The area under the concentration-time curve from 0 to infinity (AUC(0-omega)) followed a comparable pattern. Half-life (T(1/2)) was 8.8 +/- 4.2 hr and 8.2 +/- 4.3 hr after administration with water or a fatty meal (P = 1.000). Grapefruit juice shortened T(1/2) by 46% (P = 0.026). We hypothesize that albendazole is metabolized by CYP3A4 enzymes in the intestinal mucosa. This process can be inhibited by grapefruit juice. Cimetidine decreased albendazole bioavailability.