title: Absorption, excretion, and metabolism of a potential GABA-A α2/3 receptor modulator in rats.
abstract: 4-Amino-8-(2,5-dimethoxyphenyl)-N-propylcinnoline-3-carboxamide (AZD6280) is a selective GABA-A(α2/3) receptor modulator under development for the treatment of generalized anxiety disorders. Absorption, metabolism, and excretion of [(14)C]-AZD6280 was studied in rats following a single oral (7 mg/kg) or intravenous (i.v., 1 mg/kg) administration of [(14)C]-AZD6280. The results from the bile duct-cannulated study revealed that AZD6280 was well-absorbed in rats. The pharmacokinetic analysis was conducted using unlabelled parent drug that was rapidly absorbed (plasma T(max) ~1 h) and exhibited a mean apparent terminal half-life of ~4.2 h. The overall mean recoveries in the excreta were 98.6% and 100.3% after oral and i.v. administration of [(14)C]-AZD6280, respectively. The major route for elimination of [(14)C]-AZD6280 and its metabolites was through faeces. The radiochromatographic analysis of the excreta demonstrated that AZD6280 underwent extensive biotransformation. A total of 28 metabolites of AZD6280 were detected and profiled in urine, bile, and faeces in this study. The structures of metabolites were elucidated by high-resolution tandem mass spectrometry. Similar metabolite profiles were observed in rats given AZD6280 orally or intravenously.
authors.affiliation: Clinical Pharmacology & DMPK, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19803, USA. jian.guo@astrazeneca.com
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.forename: Patty C
authors.initials: PC
authors.lastname: Davis
authors.forename: Chungang
authors.initials: C
authors.lastname: Gu
authors.forename: Scott W
authors.initials: SW
authors.lastname: Grimm
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D000818:Animals; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: D000577:Amides; D011963:Receptors, GABA-A