Metabolic disposition and pharmacokinetics of pelrinone, a new cardiotonic drug, in laboratory animals and man

Abstract

The metabolic disposition of pelrinone, a cardiotonic drug, was studied in mouse, rat, rabbit, dog, monkey and man. Pelrinone was rapidly and extensively absorbed in rodents, dogs, monkeys and man. Except in rabbits, the major portion of the serum radioactivity was due to parent drug. Pelrinone was moderately bound to human serum proteins and weakly bound to serum proteins from animals. Radioactive compounds were rapidly eliminated from rat tissues with the highest concentrations found in organs associated with absorption and elimination. After a 1.0 mg/kg i.v. dose, the rapid elimination of pelrinone from mouse, rat and dog serum precluded estimation of an elimination half life (t1/2). However, after higher oral or i.v. doses, a more prolonged elimination phase was apparent and the t1/2 of pelrinone ranged from 8-10 h in rodents and dogs. In human subjects given escalating oral or i.v. doses of pelrinone, the elimination t1/2 was independent of dose and averaged 1-2 h. The serum AUC of pelrinone was linearly dose-related following oral doses up to 20 mg/kg in dogs and 100 mg in man. In mice, a greater proportional increase in AUC occurred between oral doses of 2-100 mg/kg while in rats, the serum AUC increased in less than proportional manner from 10-200 mg/kg p.o. In all species, radioactive compounds were excreted mainly in the urine. No metabolites were detected in dog and human urine while small amounts of unconjugated metabolites were excreted in mouse and rat urine.