Preclinical Pharmacodynamic and Pharmacokinetic Studies of Investigational New Drugs

摘要

Under this contract, pharmacokinetic, pharmacodynamic, bioavailability, and metabolism studies were conducted with the anti-malarial agent, artelinic acid. During these investigations, artesunic acid and arteether served as positive control agents. Major findings indicated that the oral bioavailability of artelinic acid in dogs was 67%; artelinic acid was extensively metabolized by dogs following either iv or oral administration; radioactivity derived from 14Cartelinic acid underwent biliary excretion; a 'no effect' dose of artelinic acid for the production of neurotoxicity in rats was 20 mg/kg/day, qd x 14; a 'no effect' dose of artelinic acid for the production of neurotoxicity in dogs was < lmg/kg/day, when given orally for 14 consecutive days; an injectable formulation of artelinic acid/lysine salt was well tolerated by dogs given daily iv doses for 7 consecutive days; the maximum tolerated dose (MTD) of artelinic acid for rats given a single iv dose was > 80 and < 160 rng/ kg; the MTD of artesunic acid for rats given a single iv dose was >200 and <400 mg/kg; no neurohistopathological lesions were observed for rats given <37.5 mg/ kg/day, qd x 7, of artelinic acid or up to 150 mg/kg/day, qd x 7, of artesunic acid.