The role of drug metabolism in drug discovery: a case study in the selection of an oxytocin receptor antagonist for development

Toxicol Pathol. 1995 Mar-Apr;23(2):124-30. doi: 10.1177/019262339502300204.


Drug discovery is a process involving multiple disciplines and interests. During the research phase of drug discovery, usually a large number of compounds are evaluated for biological activity and toxicological potential in animal species. Various types of problems with respect to pharmacodynamics, pharmacokinetics, and toxicity are commonly encountered at this stage. Drug metabolism, as a discipline participating in a drug discovery team, can play an important role in identifying factors underlying the problems, facilitate the optimal selection of compounds for further development, provide information on metabolites for possible improvement in drug design, and contribute to the identification of the appropriate animal species for subsequent toxicity testing. During the process of evaluating oxytocin receptor antagonists for further development for treatment of preterm labor, in vivo and in vitro drug metabolism studies conducted in rats, dogs, and monkeys contributed to the selection of L-368,899 as the development candidate on the basis of pharmacokinetic and metabolism observations. The presence of active N-demethylated metabolites of two other equipotent compounds in rats and dogs was found to be the major factor responsible for the discrepancy between oral bioavailability and efficacies observed for these 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 responsible for the poor bioavailability (< 1%) in rhesus monkeys. In vitro metabolism studies with hepatic microsomes from rats, dogs, monkeys, and humans substantiated the conclusion that the rate of hepatic metabolism of L-368,899 in monkeys is faster than in the other species.

Publication types

  • Review

MeSH terms

  • Animals
  • Camphanes / pharmacokinetics
  • Chemistry, Pharmaceutical
  • Humans
  • Macaca mulatta
  • Pharmaceutical Preparations / metabolism*
  • Piperazines / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Oxytocin / antagonists & inhibitors*
  • Tocolytic Agents / pharmacokinetics


  • Camphanes
  • Pharmaceutical Preparations
  • Piperazines
  • Receptors, Oxytocin
  • Tocolytic Agents
  • L 368899