Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R, 6R)-hydroxynorketamine. (January 2019)

• Record Type: Journal Article
• Authors: Highland, Jaclyn N; Morris, Patrick J; Zanos, Panos; Lovett, Jacqueline; Ghosh, Soumita; Wang, Amy Q; Zarate, Carlos A; Thomas, Craig J; Moaddel, Ruin; Gould, Todd D
• Is Part Of: Journal of psychopharmacology. Volume 33:Number 1(2019)
• Page Start: 12
• Page End: 24
• Publication Date: 2019-01
• Subjects: Ketamine -- hydroxynorketamine -- depression -- metabolite -- pharmacokinetics -- oral bioavailability; Psychopharmacology -- Periodicals; 615.78
• DOI: 10.1177/0269881118812095
• Languages: English
• ISSNs: 0269-8811

Abstract

Background: ( R, S )-ketamine has gained attention for its rapid-acting antidepressant actions in patients with treatment-resistant depression. However, widespread use of ketamine is limited by its side effects, abuse potential, and poor oral bioavailability. The ketamine metabolite, ( 2R, 6R )-hydroxynorketamine, exerts rapid antidepressant effects, without ketamine's adverse effects and abuse potential, in rodents. Methods: We evaluated the oral bioavailability of ( 2R, 6R )-hydroxynorketamine in three species (mice, rats, and dogs) and also evaluated five candidate prodrug modifications for their capacity to enhance the oral bioavailability of ( 2R, 6R )-hydroxynorketamine in mice. Oral administration of ( 2R, 6R )-hydroxynorketamine was assessed for adverse behavioral effects and for antidepressant efficacy in the mouse forced-swim and learned helplessness tests. Results: ( 2R, 6R )-hydroxynorketamine had absolute bioavailability between 46–52% in mice, 42% in rats, and 58% in dogs. Compared to intraperitoneal injection in mice, the relative oral bioavailability of ( 2R, 6R )-hydroxynorketamine was 62%, which was not improved by any of the candidate prodrugs tested. Following oral administration, ( 2R, 6R )-hydroxynorketamine readily penetrated the brain, with brain to plasma ratios between 0.67–1.2 in mice and rats. Oral administration of ( 2R, 6R )-hydroxynorketamine to mice did not alter locomotor activity or precipitate behaviors associated with discomfort, sickness, or stereotypy up to a dose of 450 mg/kg. Oral ( 2R, 6R )-hydroxynorketamine reduced forced-swim test immobility time (15–150 mg/kg) and reversed learned helplessness (50–150 mg/kg) in mice. Conclusions: These results demonstrate that ( 2R, 6R )-hydroxynorketamine has favorable oral bioavailability in three species and exhibits antidepressant efficacy following oral administration in mice.