Pharmacokinetics, metabolism and excretion of [¹⁴C]-lanicemine (AZD6765), a novel low-trapping N-methyl-d-aspartic acid receptor channel blocker, in healthy subjects

Abstract

1. (1S)-1-phenyl-2-(pyridin-2-yl)ethanamine (lanicemine; AZD6765) is a low-trapping N-methyl-d-aspartate (NMDA) channel blocker that has been studied as an adjunctive treatment in major depressive disorder. The metabolism and disposition of lanicemine was determined in six healthy male subjects after a single intravenous infusion dose of 150 mg [¹⁴C]-lanicemine.

2. Blood, urine and feces were collected from all subjects. The ratios of C_max and AUC_(0–∞) of lanicemine to plasma total radioactivity were 84 and 66%, respectively, indicating that lanicemine was the major circulating component with T_1/2 at 16 h. The plasma clearance of lanicemine was 8.3 L/h, revealing that lanicemine is a low-clearance compound. The mean recovery of radioactivity from urine was 93.8% of radioactive dose.

3. In urine samples, 10 metabolites of lanicemine were identified. Among which, an O-glucuronide conjugate (M1) was the most abundant metabolite (∼11% of the dose in excreta). In plasma, the circulatory metabolites were identified as a para-hydroxylated metabolite (M1), an O-glucuronide (M2), an N-carbamoyl glucuronide (M3) and an N-acetylated metabolite (M6). The average amount of each of metabolite was less than 4% of total radioactivity detected in plasma or urine.

4. In conclusion, lanicemine is a low-clearance compound. The unchanged drug and metabolites are predominantly eliminated via urinary excretion.

• Antidepressant
• major depressive disorder
• (1S)-1-phenyl-2-(pyridin-2-yl)ethanamine

Acknowledgements

The authors acknowledge Quintiles Drug Research Unit at Guy’s Hospital (London, UK) for conduct of the clinical mass balance study; Covance Laboratories (Harrogate, UK) for determination of [¹⁴C] radioactivity in whole blood, plasma, urine and feces; BASi (US) for determination of concentration of lanicemine in human plasma and urine; and other colleagues for their contributions to this study.

Declaration of interest

This study was sponsored by AstraZeneca Pharmaceuticals.