Absorption, excretion, and metabolism of a potential GABA-A a2/3 receptor modulator in rats.

Xenobiotica; the fate of foreign compounds in biological systems

PubMedID: 21210737

Guo J, Davis PC, Gu C, Grimm SW. Absorption, excretion, and metabolism of a potential GABA-A a2/3 receptor modulator in rats. Xenobiotica. 2011;41(5):385-99.
4-Amino-8-(2,5-dimethoxyphenyl)-N-propylcinnoline-3-carboxamide (AZD6280) is a selective GABA-A(a2/3) 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.