TY - JOUR T1 - Evaluation of Metabolism and Disposition of GDC-0152 in Rats Using <sup>14</sup>C Labeling Strategy at Two Different Positions: A Novel Formation of Hippuric Acid from 4-Phenyl-5-Amino-1,2,3-Thiadiazole JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 508 LP - 517 DO - 10.1124/dmd.112.047019 VL - 41 IS - 2 AU - Qin Yue AU - Teresa Mulder AU - Patrick J. Rudewicz AU - Eric Solon AU - Nageshwar Budha AU - Joseph A Ware AU - Joseph Lyssikatos AU - Cornelis E.C.A. Hop AU - Harvey Wong AU - S. Cyrus Khojasteh Y1 - 2013/02/01 UR - http://dmd.aspetjournals.org/content/41/2/508.abstract N2 - The compound (S)-1-[(S)-2-cyclohexyl-2-([S]-2-[methylamino]propanamido)acetyl]-N-(4-phenyl-1,2,3-thiadiazol-5-yl)pyrrolidine-2-carboxamide (GDC-0152) is a peptidomimetic small molecule antagonist of inhibitor of apoptosis (IAP) proteins with antitumor activity. The mass balance, pharmacokinetics, tissue distribution and metabolism of GDC-0152 was investigated in rats following intravenous administration of 15 mg/kg of [14C]GDC-0152, labeled either at the terminal phenyl ring (A) or at the carbonyl of the 2-amino-2-cyclohexylacetyl moiety (B). In rats, 92.2%–95.1% of the radiolabeled GDC-0152 dose was recovered. Approximately 62.3% and 25.1% of A was excreted in urine and feces, respectively. By contrast, B was excreted almost equally in urine (27.2%), feces (32.2%), and expired air (27.5%). GDC-0152 underwent extensive metabolism, with less than 9% of the dose recovered as parent in excreta. Similarly, in plasma, GDC-0152 represented 16.7% and 7.5% of the area under the curve of the total radioactivity for A and B, respectively. The terminal half-life (t1/2) for total radioactivity was longer for B (21.2 hours) than for A (4.59 hours). GDC-0152 was highly metabolized via oxidation and amide hydrolysis, followed by subsequent sulfation and glucuronidation. The most abundant circulating metabolites were the amide hydrolyzed products, M26, M28, M30, M31, and M34, which ranged from 3.5% to 9.0% of total radioactivity. In quantitative whole-body autoradiography studies, the residence of radioactivity in tissues was longer for B than for A, which is consistent with the t1/2 of the total radioactivity in circulation. A novel 4-phenyl-5-amino-1,2,3-thiadiazole (M28) oxidative cleavage resulted in the formation of hippuric acid (M24). This biotransformation was also observed in rat hepatocyte incubations with para-substituted M28 analogs. In addition, the formation of M24 was inhibited by 1-aminobenzotriazole, which points to the involvement of P450 enzymes. ER -