title: Metabolism, pharmacokinetics and excretion of a novel hypoxia activated cytotoxic prodrug, TH-302, in rats.
abstract: The metabolism, pharmacokinetics and excretion of a hypoxically activating prodrug developed for the treatment of cancer, TH-302, were studied in rats following intravenous administration of 50 mg/kg [(14)C]-TH-302. The pharmacokinetics of TH-302 was characterized by a short half-life of 12.3 min, a high clearance of 2.29 L/h/kg and a volume of distribution of 0.627 L/kg. In intact and bile duct-cannulated rats, TH-302 was extensively metabolized with total recovery in excreta of 68.1% and 85.8%, respectively, with equal amounts excreted through urine and bile. Quantitative whole body autoradiography showed rapid distribution of [(14)C]-TH-302 associated radioactivity with the highest concentrations in the kidney and small intestinal content, suggesting significant biliary excretion and/or gut secretion. TH-302 was metabolized via (i) hydrolysis to form 2-bromoethyl amine RM3 (7.5%); (ii) monoglutathione conjugation and subsequently to the mercapturic acid RM13 (7.5%); and (iii) diglutathione conjugation followed by hydrolysis to form the dicysteine conjugate RM5 (6.5%). A large percentage (19.7%) of the dose in the excreta was associated with unidentified polar metabolites RM1 and RM2. TH-302 was the predominant circulating component in plasma and the two major metabolites in plasma were the cysteine conjugate RM8 and mercapturic acid RM13.
authors: Threshold Pharmaceuticals, Inc., South San Francisco, CA, USA. djung@thresholdpharm.com
authors: Donald
authors: D
authors: Jung
authors: Hailong
authors: H
authors: Jiao
authors: Jian-Xi
authors: JX
authors: Duan
authors: Mark
authors: M
authors: Matteucci
authors: Ronghua
authors: R
authors: Wang
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D015687:Cell Hypoxia; D006207:Half-Life; D008297:Male; D009593:Nitroimidazoles / Q000493:pharmacokinetics* / Q000633:toxicity; D010752:Phosphoramide Mustards / Q000493:pharmacokinetics* / Q000633:toxicity; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D011355:Prodrugs; C552526:TH 302