| Summary: | The aim of this research was to determine the influence of route of administration, drug formulation and modified-liver metabolism on the pharmacokinetic and metabolic patterns of benzimidazole anthelmintics in ruminants. Both route of administration and formulation dramatically affected the bioconversion of netobimin (NTB) pro-drug, N-methoxycarbonyl-N$ sp prime$-(2-nitro-5-propylphenylthio)-${ rm N} sp{ prime prime}$-(2-ethyl sulphonic acid) guanidine, and the bioavailability and disposition kinetics of its active albendazole (ABZ) metabolites in both sheep and cattle. The efficacy of NTB conversion by the gastrointestinal (GI) microflora, was markedly lower after subcutaneous (SC) administration of NTB pro-drug compared with enteral administrations in both species. Although trisamine and zwitterion formulations of NTB were bioequivalent after SC treatment, the zwitterion suspension was two-fold more bioavailable in terms of ABZ metabolites, after oral administration to cattle. ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO$ sb2$), the main metabolites found in plasma, were reversibly exchanged between plasma and GI compartments and concentrated in the abomasum. ABZ, ABZSO and ABZSO$ sb2$ were detected in the GI tract for 72 h post-NTB administration to cattle. In vitro, ABZ was oxidized into ABZSO and ABZSO$ sb2$ by liver microsomes and ruminal and ileal fluids. However, only ABZSO was reduced (back to ABZ) by these GI fluids. The rate of ABZ sulphoxidation by liver microsomes was significantly lower in cattle compared to sheep. However, while the oxidizing activity was greater in GI fluids of cattle, the reducing activity was prevalent in those of sheep. This was consistent with the higher ABZSO$ sb2$/ABZSO ratio and the markedly faster disposition of both metabolites in cattle compared to sheep. The co-administration of NTB with different oxidation-impairing compounds, largely methimazole (MTZ), in both species, resulted in an increased bioavailability and/o
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