title: Evaluation of metabolism and disposition of GDC-0152 in rats using 14C labeling strategy at two different positions: a novel formation of hippuric acid from 4-phenyl-5-amino-1,2,3-thiadiazole.
abstract: 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 [(14)C]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 (t(1/2)) 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 t(1/2) 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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yue
authors.forename: Teresa
authors.initials: T
authors.lastname: Mulder
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Rudewicz
authors.forename: Eric
authors.initials: E
authors.lastname: Solon
authors.forename: Nageshwar
authors.initials: N
authors.lastname: Budha
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ware
authors.forename: Joseph
authors.initials: J
authors.lastname: Lyssikatos
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: S Cyrus
authors.initials: SC
authors.lastname: Khojasteh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D001345:Autoradiography; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002250:Carbon Radioisotopes; D003510:Cyclohexanes / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005243:Feces / Q000737:chemistry; D005260:Female; D006207:Half-Life; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006626:Hippurates / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006868:Hydrolysis; D007275:Injections, Intravenous; D007553:Isotope Labeling / Q000379:methods*; D008297:Male; D013058:Mass Spectrometry; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011758:Pyrroles / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014230:Triazoles / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D003510:Cyclohexanes; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006626:Hippurates; D011758:Pyrroles; D014230:Triazoles; C033020:1-aminobenzotriazole; C579046:GDC-0152; D003577:Cytochrome P-450 Enzyme System; C030514:hippuric acid