An important component of a rational drug development strategy is the correlation of toxic and therapeutic effects of investigational agents with their plasma and tissue concentrations in animals. A successful outcome of this approach depends heavily on the availability of sensitive methods for quantitating compounds in biological matrices and the careful integration of preclinical pharmacology and toxicology studies. This contract provides a continuing resource for conducting defined pharmacology studies of antitumor and anti-HIV agents under consideration by the Developmental Therapeutics Program. Analytical methods are developed to quantify compounds in plasma, urine, other biological fluids, and tissues at levels corresponding to the expected therapeutic and/or toxic range as determined from in vitro and in vivo evaluations. Plasma stability and protein binding studies are conducted at an early stage of compound development. The pharmacokinetics of test compounds are then evaluated in rodents, dogs, and non-human primates following administration by various routes and schedules, especially those intended for use in clinical trials. For some compounds, particularly anti-HIV agents, determination of oral (or other non-parenteral) bioavailability is emphasized. To provide better predictions of the human pharmacology of new agents prior to clinical trial, comparative metabolism studies are conducted with selected compounds using animal and human liver preparations. Data obtained through this contract also facilitates the application of pharmacologically-guided dose escalation strategies in Phase I clinical trials.
| Egorin, M J; Zuhowski, E G; Rosen, D M et al. (2001) Plasma pharmacokinetics and tissue distribution of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) in CD2F1 mice1. Cancer Chemother Pharmacol 47:291-302 |
| Egorin, M J; Zuhowski, E G; Sentz, D L et al. (1999) Plasma pharmacokinetics and tissue distribution in CD2F1 mice of Pc4 (NSC 676418), a silicone phthalocyanine photodynamic sensitizing agent. Cancer Chemother Pharmacol 44:283-94 |
| Egorin, M J; Rosen, D M; Wolff, J H et al. (1998) Metabolism of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) by murine and human hepatic preparations. Cancer Res 58:2385-96 |
| Egorin, M J; Rosen, D M; Benjamin, S E et al. (1997) In vitro metabolism by mouse and human liver preparations of halomon, an antitumor halogenated monoterpene. Cancer Chemother Pharmacol 41:9-14 |
