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J Psychopharmacol. 2018 Nov 29:269881118812095. doi: 10.1177/0269881118812095. [Epub ahead of print]

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

Author information

1
1 Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
2
2 Program in Toxicology, University of Maryland School of Medicine, Baltimore, MD, USA.
3
3 Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
4
4 Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
5
5 Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
6
6 Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
7
7 Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.

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.

KEYWORDS:

Ketamine; depression; hydroxynorketamine; metabolite; oral bioavailability; pharmacokinetics

PMID:
30488740
PMCID:
PMC6541551
[Available on 2020-05-29]
DOI:
10.1177/0269881118812095

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