title: The distribution and clearance of (2S,6S)-hydroxynorketamine, an active ketamine metabolite, in Wistar rats.
abstract: The distribution, clearance, and bioavailability of (2S,6S)-hydroxynorketamine has been studied in the Wistar rat. The plasma and brain tissue concentrations over time of (2S,6S)-hydroxynorketamine were determined after intravenous (20 mg/kg) and oral (20 mg/kg) administration of (2S,6S)-hydroxynorketamine (n = 3). After intravenous administration, the pharmacokinetic parameters were estimated using noncompartmental analysis and the half-life of drug elimination during the terminal phase (t 1/2) was 8.0 ± 4.0 h and the apparent volume of distribution (V d) was 7352 ± 736 mL/kg, clearance (Cl) was 704 ± 139 mL/h per kg, and the bioavailability was 46.3%. Significant concentrations of (2S,6S)-hydroxynorketamine were measured in brain tissues at 10 min after intravenous administration, ∼30 μg/mL per g tissue which decreased to 6 μg/mL per g tissue at 60 min. The plasma and brain concentrations of (2S,6S)-hydroxynorketamine were also determined after the intravenous administration of (S)-ketamine, where significant plasma and brain tissue concentrations of (2S,6S)-hydroxynorketamine were observed 10 min after administration. The (S)-ketamine metabolites (S)-norketamine, (S)-dehydronorketamine, (2S,6R)-hydroxynorketamine, (2S,5S)-hydroxynorketamine and (2S,4S)-hydroxynorketamine were also detected in both plasma and brain tissue. The enantioselectivity of the conversion of (S)-ketamine and (R)-ketamine to the respective (2,6)-hydroxynorketamine metabolites was also investigated over the first 60 min after intravenous administration. (S)-Ketamine produced significantly greater plasma and brain tissue concentrations of (2S,6S)-hydroxynorketamine relative to the (2R,6R)-hydroxynorketamine observed after the administration of (R)-ketamine. However, the relative brain tissue: plasma concentrations of the enantiomeric (2,6)-hydroxynorketamine metabolites were not significantly different indicating that the penetration of the metabolite is not enantioselective.
authors.affiliation: Laboratory of Clinical Investigation, Division of Intramural Research Programs, National Institute on Aging, National Institutes of Health Baltimore, Maryland, 21224.
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.affiliation: Laboratory of Clinical Investigation, Division of Intramural Research Programs, National Institute on Aging, National Institutes of Health Baltimore, Maryland, 21224.
authors.forename: Mitesh
authors.initials: M
authors.lastname: Sanghvi
authors.affiliation: Laboratory of Clinical Investigation, Division of Intramural Research Programs, National Institute on Aging, National Institutes of Health Baltimore, Maryland, 21224.
authors.forename: Katina Sourou Sylvestre
authors.initials: KS
authors.lastname: Dossou
authors.affiliation: Laboratory of Clinical Investigation, Division of Intramural Research Programs, National Institute on Aging, National Institutes of Health Baltimore, Maryland, 21224.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ramamoorthy
authors.affiliation: Biosciences, SRI International Menlo Park, California.
authors.forename: Carol
authors.initials: C
authors.lastname: Green
authors.affiliation: Biosciences, SRI International Menlo Park, California.
authors.forename: James
authors.initials: J
authors.lastname: Bupp
authors.affiliation: Biosciences, SRI International Menlo Park, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Swezey
authors.affiliation: Biosciences, SRI International Menlo Park, California.
authors.forename: Kathleen
authors.initials: K
authors.lastname: O'Loughlin
authors.affiliation: Laboratory of Clinical Investigation, Division of Intramural Research Programs, National Institute on Aging, National Institutes of Health Baltimore, Maryland, 21224.
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
keywords: Antidepressant; bioavailability of (2S,6S)-HNK; brain concentrations; plasma half-life and distribution of (2S,6S)-HNK