Evaluation of Pharmacokinetics of Simvastatin and Its Pharmacologically Active Metabolite from Controlled-Release Tablets of Simvastatin in Rodent and Canine Animal Models

Biotransformation of pharmacologically inactive lactone prodrug simvastatin (SV) into pharmacologically active simvastatin beta-hydroxy acid (SVA) exhibits inter-species differences due to variations in amount and activity of esterase enzymes. In this study, we investigated the pharmacokinetics (PK) of SV and its metabolite SVA following oral doses of SV from controlled-release (CR) tablets and immediate-release (IR) tablets in rodent and canine animal models that features different esterase activity. In rat PK study, no SV was detected in plasma for both formulations due to rapid hydrolysis of SV into SVA by plasma esterase. Besides, no significant differences in PK parameters of SV or SVA were observed between both species. In dog PK study, the relative oral bioavailability of CR tablets in terms of SV was 72.3% compared to IR tablets. Regarding formulation differences in dogs, CR tablets exhibited significantly lower C(max)(p<0.05), and higher T(max) (p<0.01) and MRT (p