Received for publication October 26, 2007.
Revised May 21, 2008.
Accepted for publication May 21, 2008.

Comparative disposition and metabolism of paraherquamide in sheep, gerbils and dogs

Abstract

The disposition and metabolism of paraherquamide (PHQ), a potent and broad spectrum anthelminthic, were examined in sheep, dogs and gerbils. The metabolism of PHQ in these species was extensive and marked by significant species differences both in vitro and in vivo. In sheep and gerbils, PHQ metabolism occurs mainly at the pyrrolidine moiety generating several metabolites that, for the most part, retained nematodicidal activity in vitro. In dogs the dioxepene group was also extensively metabolized, ultimately resulting in formation of a catechol and loss of pharmacological activity. After oral administration of [³H]PHQ to intact sheep, gerbils and dogs the majority of the administered radioactivity was recovered in feces. Intact PHQ accounted for 0% (dog) to 30% (sheep, gerbil) of drug-related material in feces. A detailed investigation of the composition of the intestinal content of sheep indicated that a significant amount of the dose was still present in the rumen 24 h post-dose and that PHQ underwent significant dehydration in the cecum. The oral pharmacokinetic parameters of PHQ in sheep and dogs suggests that its absorption is rapid in both species but that its apparent elimination rate is significantly higher in the dog (t 1.5 h) than it is in sheep (t 8.5 h). The short elimination half-life and the absence of PHQ or other active components in the dog gastro-intestinal tract provide a potential explanation of the lack of efficacy of PHQ in this species.

Key words: metabolite identification, pharmacokinetics, structure elucidation