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.

Agency
National Institute of Health (NIH)
Institute
Division of Cancer Treatment (NCI)
Type
Research and Development Contracts (N01)
Project #
N01CM057201-015
Application #
6356772
Study Section
Project Start
1994-12-01
Project End
1999-11-30
Budget Start
2000-09-25
Budget End
1999-11-30
Support Year
Fiscal Year
2000
Total Cost
$8,122
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Snapka, R M; Gao, H; Grabowski, D R et al. (2001) Cytotoxic mechanism of XK469: resistance of topoisomerase IIbeta knockout cells and inhibition of topoisomerase I. Biochem Biophys Res Commun 280:1155-60
Huang, K C; Gao, H; Yamasaki, E F et al. (2001) Topoisomerase II poisoning by ICRF-193. J Biol Chem 276:44488-94
Li, Z; Chan, K K (2000) A subnanogram API LC/MS/MS quantitation method for depsipeptide FR901228 and its preclinical pharmacokinetics. J Pharm Biomed Anal 22:33-44
Gao, H; Yamasaki, E F; Chan, K K et al. (2000) Chloroquinoxaline sulfonamide (NSC 339004) is a topoisomerase IIalpha/beta poison. Cancer Res 60:5937-40
Gao, H; Huang, K C; Yamasaki, E F et al. (1999) XK469, a selective topoisomerase IIbeta poison. Proc Natl Acad Sci U S A 96:12168-73
Chan, K K; Bakhtiar, R; Jiang, C (1997) Depsipeptide (FR901228, NSC-630176) pharmacokinetics in the rat by LC/MS/MS. Invest New Drugs 15:195-206