{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:00:39Z","timestamp":1791388839771,"version":"4.3.3"},"reference-count":53,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2018,11,29]],"date-time":"2018-11-29T00:00:00Z","timestamp":1543449600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018576","name":"Harrington Discovery Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100018576","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["MH107615"],"award-info":[{"award-number":["MH107615"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM008181"],"award-info":[{"award-number":["GM008181"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Psychopharmacol"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>( 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\u2019s adverse effects and abuse potential, in rodents.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>( 2R,6R)-hydroxynorketamine had absolute bioavailability between 46\u201352% 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\u20131.2 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\u2013150 mg\/kg) and reversed learned helplessness (50\u2013150 mg\/kg) in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>These results demonstrate that ( 2R,6R)-hydroxynorketamine has favorable oral bioavailability in three species and exhibits antidepressant efficacy following oral administration in mice.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/0269881118812095","type":"journal-article","created":{"date-parts":[[2018,11,29]],"date-time":"2018-11-29T08:27:07Z","timestamp":1543480027000},"page":"12-24","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":57,"title":["Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (\n                    <i>2R,6R<\/i>\n                    )-hydroxynorketamine"],"prefix":"10.1177","volume":"33","author":[{"given":"Jaclyn N","family":"Highland","sequence":"first","affiliation":[{"name":"Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA"},{"name":"Program in Toxicology, University of Maryland School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J","family":"Morris","sequence":"additional","affiliation":[{"name":"Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panos","family":"Zanos","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Lovett","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumita","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy Q","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Carlos A","family":"Zarate","sequence":"additional","affiliation":[{"name":"Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig 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