title: Fasciola hepatica: mebendazole and thiabendazole pharmacokinetics in sheep.
abstract: Pharmacokinetics of the two anthelmintic drugs mebendazole and thiabendazole were determined in sheep before and 4, 8, 13, 19, and 25 weeks after an infestation of animals by an oral administration of 150 metacercariae of Fasciola hepatica. The parasitic pathology was ascertained by the increase in plasma enzyme activities of glutamate dehydrogenase and gamma-glutamyltransferase. After oral administration of mebendazole (25 mg.kg-1), the parent drug and especially its reduced metabolite 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 postinfection. This change was related to decreases in both the elimination from the pharmacokinetic compartment representing the reduced metabolite and the area under the curve of plasma metabolite concentration versus time. A 59% decrease in MBZ reduction was demonstrated in liver microsomes prepared from 12-week-infected sheep. This reductase activity was characterized by NADPH dependency and a pH peak activity of 6.0 and was competitively inhibited by daunomycin. In sheep receiving a 50 mg.kg-1 oral dose of thiabendazole, fascioliasis provoked only decreased plasma concentrations of the metabolite 5-hydroxythiabendazole by Weeks 4 to 25 postinfection. This change parallels an increase in urinary 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 effect on the pharmacokinetics of mebendazole, a drug intensively metabolized by the liver into a metabolite present at high concentrations in the plasma of animals and humans.
authors.affiliation: Laboratoire de Pharmacologie-Toxicologie, INRA, Toulouse, France.
authors.forename: P
authors.initials: P
authors.lastname: Galtier
authors.forename: M
authors.initials: M
authors.lastname: Coulet
authors.forename: J F
authors.initials: JF
authors.lastname: Sutra
authors.forename: B
authors.initials: B
authors.lastname: Biro-Sauveur
authors.forename: M
authors.initials: M
authors.lastname: Alvinerie
mesh_terms: D000284:Administration, Oral; D000818:Animals; D005211:Fascioliasis / Q000188:drug therapy / Q000378:metabolism / Q000662:veterinary*; D005969:Glutamate Dehydrogenase / Q000097:blood; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000469:parasitology; D008297:Male; D008463:Mebendazole / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008862:Microsomes, Liver / Q000201:enzymology; D010084:Oxidation-Reduction; D012756:Sheep; D012757:Sheep Diseases / Q000188:drug therapy / Q000378:metabolism*; D013827:Thiabendazole / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D008463:Mebendazole; D005969:Glutamate Dehydrogenase; D005723:gamma-Glutamyltransferase; D013827:Thiabendazole