THE ROLE OF DRUG-METABOLISM IN DRUG DISCOVERY - A CASE-STUDY IN THE SELECTION OF AN OXYTOCIN RECEPTOR ANTAGONIST FOR DEVELOPMENT

Drug discovery is a process involving multiple disciplines and interes ts. During the research phase of drug discovery, usually a large numbe r of compounds are evaluated for biological activity and toxicological potential in animal species. Various types of problems with respect t o pharmacodynamics, pharmacokinetics, and toxicity are commonly encoun tered at this stage. Drug metabolism, as a discipline participating in a drug discovery team, can play an important role in identifying fact ors underlying the problems, facilitate the optimal selection of compo unds for further development, provide information on metabolites for p ossible improvement in drug design, and contribute to the identificati on of the appropriate animal species for subsequent toxicity testing. During the process of evaluating oxytocin receptor antagonists for fur ther development for treatment of preterm labor, in vivo and in vitro drug metabolism studies conducted in rats, dogs, and monkeys contribut ed to the selection of L-368,899 as the development candidate on the b asis of pharmacokinetic and metabolism observations. The presence of a ctive N-demethylated metabolites of two other equipotent compounds in rats and dogs was found to be the major factor responsible for the dis crepancy between oral bioavailability and efficacies observed for thes e 2 compounds. For L-368,899, a compound that demonstrated 20-40% oral bioavailability in rats, dogs, and chimpanzees, extensive first-pass metabolism rather than absorption was determined as the major factor r esponsible for the poor bioavailability (<1%) in rhesus monkeys. In vi tro metabolism studies with hepatic microsomes from rats, dogs, monkey s, and humans substantiated the conclusion that the rate of hepatic me tabolism of L-368,899 in monkeys is faster than in the other species.