title: Subchronic administration of (R,S)-ketamine induces ketamine ring hydroxylation in Wistar rats.
abstract: Subchronic administration of (R,S)-ketamine, (R,S)-Ket, is used in the treatment of neuropathic pain, in particular Complex Regional Pain Syndrome, but the effect of this protocol on the metabolism of (R,S)-Ket is unknown. In this study, daily administration of a low dose of (R,S)-Ket for 14-days to Wistar rats was conducted to determine the impact of sub-chronic dosing on the pharmacokinetics of (R,S)-Ket and its major metabolites. The data indicate that, relative to a single administration of (R,S)-Ket, subchronic administration resulted in increased clearance of (R,S)-Ket and the N-demethylated metabolite norketamine measured as elimination half-life (t1/2) and decreased plasma concentrations of these compounds. Subchronic administration produced a slight decrease in t1/2 and an increase in plasma concentration of the major metabolite, (2S,6S;2R,6R)-hydroxynorketamine, and produced significant increases in the plasma concentrations of the (2S,6R;2R,6S)-hydroxynorketamine and (2S,4R;2R,4S)-hydroxynorketamine metabolites. The metabolism of (R,S)-Ket predominately occurs via two microsomal enzyme-mediated pathways: (R,S)-Ket⇒(R,S)-norketamine⇒(2S,6S;2R,6R)-hydroxynorketamine and (2S,4R;2R,4S)-hydroxynorketamine and the (R,S)-Ket⇒(2S,6R;2R,6S)-hydroxyketamine⇒(2S,6R;2R,6S)-hydroxynorketamine and (2S,6S;2R,6R)-hydroxynorketamine. The results indicate that the activity of both metabolic pathways are increased by subchronic administration of (R,S)-Ket producing new metabolite patterns and potential differences in clinical effects.
authors.affiliation: Laboratory of Clinical Investigation, National institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: R
authors.initials: R
authors.lastname: Moaddel
authors.affiliation: Laboratory of Clinical Investigation, National institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sanghvi
authors.affiliation: Laboratory of Clinical Investigation, National institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ramamoorthy
authors.affiliation: Department of Biopharmacy, Medical University of Lublin, Lublin, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Jozwiak
authors.affiliation: Laboratory of Clinical Investigation, National institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: N
authors.initials: N
authors.lastname: Singh
authors.affiliation: SRI International, Menlo Park, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Green
authors.affiliation: SRI International, Menlo Park, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: O'Loughlin
authors.affiliation: Cooper University Hospital, Robert Wood Johnson Medical School, UMDNJ, Department of Anesthesiology, USA.
authors.forename: M
authors.initials: M
authors.lastname: Torjman
authors.affiliation: Laboratory of Clinical Investigation, National institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA; Mitchell Woods Pharmaceuticals, Shelton, CT, USA. Electronic address: iwwainer@mitchellwoods.com.
authors.forename: I W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D000700:Analgesics / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006900:Hydroxylation; D007274:Injections, Intraperitoneal; D007649:Ketamine / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D017208:Rats, Wistar; D013237:Stereoisomerism
chemical_list: D000700:Analgesics; D007649:Ketamine
keywords: (2S,6R)-hydroxynorketamine; Complex Regional Pain Syndrome; Neuropathic pain