Absorption, excretion, and metabolism of a potential GABA-A_α2/3 receptor modulator in rats

Abstract

1. 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 [¹⁴C]-AZD6280 was studied in rats following a single oral (7 mg/kg) or intravenous (i.v., 1 mg/kg) administration of [¹⁴C]-AZD6280.

2. The results from the bile duct-cannulated study revealed that AZD6280 was well-absorbed in rats.

3. 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.

4. The overall mean recoveries in the excreta were 98.6% and 100.3% after oral and i.v. administration of [¹⁴C]-AZD6280, respectively. The major route for elimination of [¹⁴C]-AZD6280 and its metabolites was through faeces.

5. 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.

Keywords::

• AZD6280
• metabolism
• excretion
• mass spectrometry

Acknowledgement

We thank Dr. Mingli Zhang, Dr. Charles S. Elmore, Dr. Li Liang, Dawn M. Perry, and other colleagues for their contributions to this study, Covance laboratories (Madison, WI) for the conduct of the rat studies.

Declaration of interest

The studies reported here were supported by AstraZeneca Pharmaceuticals LP. All of the authors are employees of AstraZeneca Pharmaceuticals LP. The authors report no conflict of interest.