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The distribution and clearance of (2S,6S)-hydroxynorketamine, an active ketamine metabolite, in Wistar rats.

Moaddel R, Sanghvi M, Dossou KS, Ramamoorthy A, Green C, Bupp J, Swezey R, O'Loughlin K, Wainer IW - Pharmacol Res Perspect (2015)

Bottom Line: 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).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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Clinical Investigation, Division of Intramural Research Programs, National Institute on Aging, National Institutes of Health Baltimore, Maryland, 21224.

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.

No MeSH data available.


Scheme Metabolic pathway of ketamine.
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fig03: Scheme Metabolic pathway of ketamine.

Mentions: (R,S)-Ket was developed as an anesthetic agent and more recently has been shown to be effective for the clinical treatment of treatment-resistant major depressive disorder and bipolar depression at subanesthetic doses of (R,S)-Ket or (S)-Ket (Paul et al. 2009; Zarate et al. 2012; Zhao et al. 2012; Hirota and Lambert, 2011). The initial pharmacodynamic studies of (R,S)-Ket were conducted using Wistar rats and examined the anesthetic effects of the parent compound and its two principle metabolites (R,S)-norketamine, (R,S)-norKet, and (2S,6S;2R,6R)-hydroxynorketamine, (2S,6S;2R,6R)-HNK, Scheme 3, Pathway A (Leung and Baillie 1986). The results demonstrated that (R,S)-Ket and (R,S)-norKet produced the central nervous system (CNS) activities associated with general anesthesia and increased spontaneous locomotor activity during the postanesthetic recovery phase, whereas(2S,6S;2R,6R)-HNK had no effect. (2S,6S;2R,6R)-HNK was described as an “inactive” metabolite.


The distribution and clearance of (2S,6S)-hydroxynorketamine, an active ketamine metabolite, in Wistar rats.

Moaddel R, Sanghvi M, Dossou KS, Ramamoorthy A, Green C, Bupp J, Swezey R, O'Loughlin K, Wainer IW - Pharmacol Res Perspect (2015)

Scheme Metabolic pathway of ketamine.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492732&req=5

fig03: Scheme Metabolic pathway of ketamine.
Mentions: (R,S)-Ket was developed as an anesthetic agent and more recently has been shown to be effective for the clinical treatment of treatment-resistant major depressive disorder and bipolar depression at subanesthetic doses of (R,S)-Ket or (S)-Ket (Paul et al. 2009; Zarate et al. 2012; Zhao et al. 2012; Hirota and Lambert, 2011). The initial pharmacodynamic studies of (R,S)-Ket were conducted using Wistar rats and examined the anesthetic effects of the parent compound and its two principle metabolites (R,S)-norketamine, (R,S)-norKet, and (2S,6S;2R,6R)-hydroxynorketamine, (2S,6S;2R,6R)-HNK, Scheme 3, Pathway A (Leung and Baillie 1986). The results demonstrated that (R,S)-Ket and (R,S)-norKet produced the central nervous system (CNS) activities associated with general anesthesia and increased spontaneous locomotor activity during the postanesthetic recovery phase, whereas(2S,6S;2R,6R)-HNK had no effect. (2S,6S;2R,6R)-HNK was described as an “inactive” metabolite.

Bottom Line: 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).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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Clinical Investigation, Division of Intramural Research Programs, National Institute on Aging, National Institutes of Health Baltimore, Maryland, 21224.

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.

No MeSH data available.