title: Pharmacokinetics, metabolism and excretion of [(14)C]-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 [(14)C]-lanicemine. 2.Blood, urine and feces were collected from all subjects. The ratios of Cmax and AUC(0-∞) of lanicemine to plasma total radioactivity were 84 and 66%, respectively, indicating that lanicemine was the major circulating component with T1/2 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.
authors.affiliation: DMPK of Infection Innovative Medicine, AstraZeneca Pharmaceuticals , Waltham, MA , USA and.
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.forename: Diansong
authors.initials: D
authors.lastname: Zhou
authors.forename: Scott W
authors.initials: SW
authors.lastname: Grimm
authors.forename: Khanh H
authors.initials: KH
authors.lastname: Bui
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D002250:Carbon Radioisotopes; D005243:Feces / Q000737:chemistry*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D055442:Metabolome; D008875:Middle Aged; D010627:Phenethylamines / Q000032:analysis / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D011725:Pyridines / Q000032:analysis / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
chemical_list: C585977:AZD6765; D002250:Carbon Radioisotopes; D010627:Phenethylamines; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate
keywords: (1S)-1-phenyl-2-(pyridin-2-yl)ethanamine; Antidepressant; major depressive disorder