title: Metabolism and excretion of TH-302 in dogs.
abstract: 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.
authors.affiliation: Threshold Pharmaceuticals, Inc., South San Francisco, CA 94080, USA. djung@thresholdpharm.com
authors.forename: Donald
authors.initials: D
authors.lastname: Jung
authors.forename: Hailong
authors.initials: H
authors.lastname: Jiao
authors.forename: Jian-Xi
authors.initials: JX
authors.lastname: Duan
authors.forename: Mark
authors.initials: M
authors.lastname: Matteucci
authors.forename: Ronghua
authors.initials: R
authors.lastname: Wang
mesh_terms: D000818:Animals; D019540:Area Under Curve; D004285:Dogs; D005021:Ethylamines / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D009593:Nitroimidazoles / Q000378:metabolism*; D010752:Phosphoramide Mustards / Q000378:metabolism*
chemical_list: D005021:Ethylamines; D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; C552526:TH 302; C041564:ethylamine