Pharmacokinetics and metabolism of SK&F 86002 in male and female Sprague-Dawley rats

Abstract

Several pharmacokinetic parameters for SK&F 86002 [6-(4'-fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo(2,1-b)-thia zole] and its metabolites (sulfoxide, sulfone) were measured in male and female Sprague-Dawley rats after iv (5 mg/kg) and a wide range (10-80 mg/kg) of oral doses of SK&F 86002. In both sexes. SK&F 86002 is metabolized to an active metabolite, sulfone, which has an extended half-life (approximately 13 hr) and, therefore, has the potential to accumulate upon repeated dosing. In addition, striking differences between sexes were noted in several of the pharmacokinetic parameters measured. The AUCs areas under the plasma concentration time curves, for SK&F 86002 in female rats obtained at the higher doses of SK&F 86002 were substantially greater than expected, when compared with lower doses in female rats or with equivalent doses in male rats. Furthermore, at all doses of SK&F 86002, AUCs for sulfoxide were substantially larger in female than in male rats. Consequently, the systemic exposure to SK&F 86002 and metabolites is substantially greater in female rats than in male rats. Therefore, extrapolation of the pharmacologic and toxicologic sequelae of SK&F 86002, observed at larger doses in female rats, to lower doses should be approached cautiously. Furthermore, the extended half-life of the pharmacologically active sulfone metabolite of SK&F 86002 suggests that this metabolite could accumulate on repeated daily dosing of SK&F 86002 and could, therefore, account for much of the chronic pharmacologic and toxicologic activity of SK&F 86002.