FASCIOLA-HEPATICA - MEBENDAZOLE AND THIABENDAZOLE PHARMACOKINETICS INSHEEP

Pharmacokinetics of the two anthelmintic drugs mebendazole and thiaben dazole were determined in sheep before and 4, 8, 13, 19, and 25 weeks after an infestation of animals by an oral administration of 150 metac ercariae of Fasciola hepatica. The parasitic pathology was ascertained by the increase in plasma enzyme activities of glutamate dehydrogenas e and gamma-glutamyltransferase. After oral administration of mebendaz ole (25 mg.kg(-1)), the parent drug and especially its reduced metabol ite were present in plasma of animals. A significant 1.5- to 2.7-fold increase in the mean residence time occurred by Weeks 13 to 25 postinf ection. This change was related to decreases in both the elimination f rom the pharmacokinetic compartment representing the reduced metabolit e and the area under the curve of plasma metabolite concentration vers us time. A 59% decrease in MBZ reduction was demonstrated in liver mic rosomes prepared from 12-week-infected sheep. This reductase activity was characterized by NADPH dependency and a pH peak activity of 6.0 an d was competitively inhibited by daunomycin. In sheep receiving a 50 m g.kg(-1) oral dose of thiabendazole, fascioliasis provoked only decrea sed plasma concentrations of the metabolite 5-hydroxythiabendazole by Weeks 4 to 25 postinfection. This change parallels an increase in urin ary excretion of free metabolite but this is of minor significance in the general fate of the drug because of the prevalence of excretion as conjugates. In summary, fascioliasis appears to have more of an effec t on the pharmacokinetics of mebendazole, a drug intensively metaboliz ed by the liver into a metabolite present at high concentrations in th e plasma of animals and humans. (C) 1994 Academic Press, Inc.