The Role of Drug Metabolism in Drug Discovery: A Case Study in the Selection of an Oxytocin Receptor Antagonist for Development

Abstract

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.

A Comprehensive Quantitative and Qualitative Evaluation of Extrapolation of Intravenous Pharmacokinetic Parameters From Rat, Dog, and Monkey to Humans. I. Clearance

“…From a resource and ethical perspective, minimizing the use of nonhuman primates is an important overall goal (Animal Procedures Committee, 2002). Additionally, there have been reports of specific compounds for which monkey pharmacokinetics were not representative of human disposition (Krause and Kühne, 1993;Tanaka et al, 1994;Chiu et al, 1995;Kuroda et al, 2000), and Chiou and Buehler (2002) have recently proposed on the basis of a ϳ30-compound data set that monkeys may systematically overpredict human clearance. However, from the present investigation using a 103-compound data set, it is clear that extrapolation methods using monkey pharmacokinetic data provide the most qualitatively and quantitatively accurate estimate of human clearance.…”

Quantitation of drug metabolites in the absence of pure metabolite standards by high‐performance liquid chromatography coupled with a chemiluminescence nitrogen detector and mass spectrometer

“…The metabolite concentration was determined to be 984 nM according to the peak area and the nitrogen ratio by using Eqn. (1). From the MRM response, we could calculate the equimolar MRM response ratio for the metabolite over the BMS compound in urine was 0.18.…”

“…Quantitative or semi-quantitative information on metabolites with pharmacological and/or toxicological activities plays an important role at the drug discovery stage in identifying factors that may underlie potential problems. 1,2 One of the most frequently used methods in the pharmaceutical industry for quantitative determination of drugs and their metabolites in biological matrices is high-performance liquid chromatography/tandem mass spectrometry (HPLC/ MS/MS), [3][4][5][6] mostly because of its proven speed, selectivity, and sensitivity. However, one of the limitations of this technique is that response can be very sensitive to small variations in chemical structure.…”

Considerations in the Design of Toxicokinetic Programs

“…The issues involved in TK support of chronic (6)(7)(8)(9)(10)(11)(12) (45). Coupled with the scientific inadequacy of the rodent bioassay is the concern by some investigators that plasma drug/metabolite concentrations in these tests provide no rational basis for the assessment of human carcinogenic risk (31 ), while others view toxicokinetics as a tool in data interpretation (2,10 lot studies (9).…”

“…This is expanded further in this issue (14). Retrospective (ancillary) (42) (TABLE IV) During Drug Drscavery and Selection In recent years, drug metabolism has emerged to play a major role in the discovery and selection of new drugs (12,24). The type of data generated will …”