Metabolism and excretion of TH-302 in dogs.

The metabolism and excretion of a hypoxically activating prodrug for the treatment of cancer, TH-302, were studied in beagle dogs following intravenous administration of 20 mg/kg (14)C-TH-302. TH-302 was extensively metabolized with total recovery of 75.1%, with 47.5% and 25.3% excreted through the urine and through the bile into the feces, respectively. The three TH-302 metabolites in plasma were: DM7, a conjugate of TH-302 with glutathione replacing a bromine atom; DM5, a hydrolysis product of DM7 with loss of the glutamic acid moiety; and DM6, a hydrolysis product of DM5 with loss of the glycine moiety. DM6 and TH-302 were the major radioactive components in plasma and accounted for 69.8% and 27.3% of the total AUC, respectively. The major metabolite in urine was DM6, which accounted for 22.7% of the administered dose. Two other metabolites identified in urine were: DM3, a dicysteine conjugate of TH-302; and DM4, which was formed by hydrolysis and loss of the 1-methyl-2-nitro-imidazol-5-yl methoxy moiety, followed by oxidation on the cysteinyl ethylamine moiety. DM1 and DM2 in urine accounted for 6.50 and 7.76% of administered dose and were not identified. DM1 was the only fecal metabolite. Further investigations are required to completely characterize the metabolism of TH-302.

Metabolism, pharmacokinetics and excretion of a novel hypoxia activated cytotoxic prodrug, TH-302, in rats.

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.