This contract provides a resource for preclinical pharmacology investigations of antitumor and anti-HIV agents under development by the Division of Cancer Treatment and Diagnosis, NCI. Defined pharmacological studies are assigned to the contractor through a Work Assignment system. These studies may include (1) development and validation of sensitive analytical methodology for quantitation of compounds in biological fluids and tissues; (2) in vitro stability and protein binding studies; (3) comparative in vitro metabolism studies using animal and human tissue preparations and expressed CYP450 isoforms; (4) determination of pharmacokinetic profiles and derived parameters following intravenous, intraperitoneal, subcutaneous (bolus and/or infusion) and oral dosing in rodents, dogs, and non-human primates; and (5) identification and pharmacokinetic analysis of drug metabolites. Data obtained in these studies are used to determine the most appropriate route, dose, and schedule of administration for achieving sustained therapeutic concentrations of an agent in biological fluids. For some compounds, particularly cytostatic antitumor or anti-HIV agents (which may be administered to patients for long periods of time), determination of oral bioavailability is emphasized. Preclinical pharmacology studies are generally performed in parallel with (and are designed to aid in the interpretation of) preclinical toxicology evaluations. Together, these investigations provide necessary data for IND filing as well as a rational basis for the clinical Phase I starting dose and dose escalation scheme.
| Reid, Joel M; Buhrow, Sarah A; Gilbert, Judith A et al. (2014) Mouse pharmacokinetics and metabolism of the curcumin analog, 4-piperidinone,3,5-bis[(2-fluorophenyl)methylene]-acetate(3E,5E) (EF-24; NSC 716993). Cancer Chemother Pharmacol 73:1137-46 |
| Reid, Joel M; Buhrow, Sarah A; Kuffel, Mary J et al. (2011) Pharmacokinetics, pharmacodynamics and metabolism of the dimeric pyrrolobenzodiazepine SJG-136 in rats. Cancer Chemother Pharmacol 68:777-86 |
| Jia, Lee; Schweikart, Karen; Tomaszewski, Joseph et al. (2008) Toxicology and pharmacokinetics of 1-methyl-d-tryptophan: absence of toxicity due to saturating absorption. Food Chem Toxicol 46:203-11 |
| Buhrow, Sarah A; Reid, Joel M; Jia, Lee et al. (2006) LC-MS/MS assay and dog pharmacokinetics of the dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501). J Chromatogr B Analyt Technol Biomed Life Sci 840:56-62 |
