Comparative Disposition and Metabolism of Paraherquamide in Sheep, Gerbils, and Dogs

Abstract

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 [ 3 H]PHQ to intact sheep, gerbils, and dogs, the majority of the administered radioactivity was recovered in feces. Intact PHQ accounted for 0%(dogs) to ϳ30% (sheep and gerbils) 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 after dose and that PHQ underwent significant dehydration in the cecum. The oral pharmacokinetic parameters of PHQ in sheep and dogs suggest that its absorption is rapid in both species but that its apparent elimination rate is significantly higher in the dog (t 1/2 ϳ 1.5 h) than it is in sheep (t 1/2 ϳ 8.5 h). The short elimination half-life and the absence of PHQ or other active components in the dog gastrointestinal tract provide a potential explanation of the lack of efficacy of PHQ in this species.

Marine natural products

“…330 Paraherquaminde K has previously been reported as a metabolite in dogs. 331 A second study of P. janthinellum yielded unusual spirocyclic dioxopiperazine alkaloids penispirozines A-H 833, 834, 835-840. Penisperiozine A is particularly noteworthy as it possess a pyrazino [1,2]oxazadecaline coupled with a thiophane ring system, while penisperiozine B is a pentacyclic compound incorporating both spirothiophane and spiro-furan rings.…”

Basic and clinical pharmacology contribution to extend anthelmintic molecules lifespan

“…After oral administration of paraherquamide to lambs, rapid absorption with a peak plasma concentration between 0.5 and 2 h post-treatment was observed (Aloysius et al, 2008). Paraherquamide undergoes extensive liver metabolism, showing a plasma elimination half-life of 8.5 h. Eighty % of the dose is excreted in faeces largely as metabolic products (Aloysius et al, 2008). In an attempt to optimize the spectrum of its anthelmintic activity, derquantel has been registered for distribution in combination with abamectin (Little et al, 2011).…”

“…However, the pharmacokinetic behaviour of paraherquamide has been described in sheep and could be useful in extrapolating overall kinetic features. After oral administration of paraherquamide to lambs, rapid absorption with a peak plasma concentration between 0.5 and 2 h post-treatment was observed (Aloysius et al, 2008). Paraherquamide undergoes extensive liver metabolism, showing a plasma elimination half-life of 8.5 h. Eighty % of the dose is excreted in faeces largely as metabolic products (Aloysius et al, 2008).…”

Canadian Content in the Pages ofDrug Metabolism and Disposition: A Comprehensive Historical Analysis

“…Important practical investigations from this group compared P450-mediated activities in human, dog, cat, and horse liver microsomes (Chauret et al, 1997), documented the effects of common organic solvents on P450-mediated activities in human liver microsomes (Chauret et al, 1998), and established a novel fluorogenic substrate, 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin as a selective CYP2D6 probe substrate (Chauret et al, 2001). Other Merck Frosst colleagues optimized culture conditions for assessing P450 induction in rat and human hepatocytes (Silva et al, 1998), conducted in vitro metabolism studies supporting the structural optimization of the phosphodiesterase-IV inhibitor, CDP-840 (Li et al, 2001), showed that rat hepatocytes cryopreserved by a programmed-freezing protocol retain drug transport activities (Houle et al, 2003), and reported a comparison of the metabolism and disposition of paraherquamide, a broadspectrum anthelminthic, in sheep, gerbils, and dogs (Aloysius et al, 2008).…”