Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (<i>2R,6R</i>)-hydroxynorketamine

Published on 2018-11-29T12:00:00Z (GMT) by
<div>Background:<p>(<i>R,S</i>)-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, (<i>2R,6R</i>)-hydroxynorketamine, exerts rapid antidepressant effects, without ketamine’s adverse effects and abuse potential, in rodents.</p>Methods:<p>We evaluated the oral bioavailability of (<i>2R,6R</i>)-hydroxynorketamine in three species (mice, rats, and dogs) and also evaluated five candidate prodrug modifications for their capacity to enhance the oral bioavailability of (<i>2R,6R</i>)-hydroxynorketamine in mice. Oral administration of (<i>2R,6R</i>)-hydroxynorketamine was assessed for adverse behavioral effects and for antidepressant efficacy in the mouse forced-swim and learned helplessness tests.</p>Results:<p>(<i>2R,6R</i>)-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 (<i>2R,6R</i>)-hydroxynorketamine was 62%, which was not improved by any of the candidate prodrugs tested. Following oral administration, (<i>2R,6R</i>)-hydroxynorketamine readily penetrated the brain, with brain to plasma ratios between 0.67–1.2 in mice and rats. Oral administration of (<i>2R,6R</i>)-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 (<i>2R,6R</i>)-hydroxynorketamine reduced forced-swim test immobility time (15–150 mg/kg) and reversed learned helplessness (50–150 mg/kg) in mice.</p>Conclusions:<p>These results demonstrate that (<i>2R,6R</i>)-hydroxynorketamine has favorable oral bioavailability in three species and exhibits antidepressant efficacy following oral administration in mice.</p></div>

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Highland, Jaclyn N; Morris, Patrick J; Zanos, Panos; Lovett, Jacqueline; Ghosh, Soumita; Wang, Amy Q; et al. (2018): Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine. SAGE Journals. Collection.