Abstract. 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 (C max ) 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 ‫ס‬ 0.031). When grapefruit juice was combined with cimetidine, C max was significantly lower than with grapefruit juice alone (0.41 ± 0.29 mg/l and 0.76 ± 0.37 mg/l, respectively; P ‫ס‬ 0.022). The area under the concentration-time curve from 0 to infinity (AUC 0-⍀ ) 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 ‫ס‬ 1.000). Grapefruit juice shortened T 1/2 by 46% (P ‫ס‬ 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.

Abstract. The low bioavailability of albendazole affects the therapeutic response in patients with echinococcosis. Cimetidine co-administration is reported to improve bioavailability. To analyze the assumed dose-dependent bioavailability of albendazole, we administered 5 to 30 mg/kg albendazole to 6 male volunteers in a randomized cross-over study. To assess the effect of cimetidine (10 mg/kg twice daily), the drug was given with albendazole (20 mg/kg). A dose-dependent bioavailability was not observed. This was due to inter-individual variability of the maximal concentration (C max 38%-72%) of albendazole sulphoxide (ABZSX), the active metabolite of albendazole. C max was 0.21 Ϯ 0.14 mg/L after 5 mg/kg and 0.39 Ϯ 0.19 mg/L after 30 mg/kg albendazole (P ϭ 0.217). Cimetidine tended to decrease C max by 52% (P ϭ 0.109) and significantly inhibited ABZSX breakdown as indicated by the prolongation of ABZSX elimination half-life from 7.4 Ϯ 3.3 hr to 19.0 Ϯ 11.7 hr (P ϭ 0.028). Remarkably, the inter-individual variability of C max was significantly lower during cimetidine co-administration: 14% versus 72%.

Grapefruit juice significantly increases the oral bioavailability of artemether without an effect on the elimination half-life. It suggests a role for intestinal CYP3A4 in the presystemic metabolism of artemether.

No abstract

Pluim HJ, Koppe JG, Olie K, van der Slikke JW, Slot PC, van Boxtel CJ. Clinical laboratory manifestations of exposure to background levels of dioxins in the perinatal period. Acta Paediatr 1994;83:583-7. Stockholm. ISSN 0803-5253The effects of exposure to low levels of dioxins in infants (intrauterine and via breast milk) were studied. In a group of 35 babies, specially selected, laboratory tests were performed in cord blood and in blood sampled at 7 days and 11 weeks of age. The outcome of these laboratory tests was related to dioxin concentrations in milk fat and cumulative dioxin intake. At I 1 weeks of age, alanine aminotransferase and aspartate aminotransferase activities in plasma were significantly related to cumulative dioxin intake. A significant negative relation was found between platelet count and cumulative dioxin intake. The results of this study suggest that exposure to background levels of dioxins, both intrauterine and via breast milk, may have effects in newborns. 0 Blood, dioxins, human milk, infant