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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.


Plasma profile of (2S, 6S)-6-hydroxynorketamine administered i.v. and po routes, 20 mg/kg to male wistar rats. Each data point represents the mean ± SD for n = 3 rats. Time points were collected through 72 h, but drug was not detected in plasma samples from the final time point.
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fig02: Plasma profile of (2S, 6S)-6-hydroxynorketamine administered i.v. and po routes, 20 mg/kg to male wistar rats. Each data point represents the mean ± SD for n = 3 rats. Time points were collected through 72 h, but drug was not detected in plasma samples from the final time point.

Mentions: The only compound identified in the analysis of the plasma samples obtained after the i.v. and p.o. administration of (2S,6S)-HNK was the administered (2S,6S)-HNK (data not shown). This is consistent with the data from previous studies in the rat in which the administration of (2S,6S;2R,6R)-HNK and (2S,6S)-HNK resulted in no additional Phase I metabolites or chiral inversion of an asymmetric center (Leung and Baillie 1986; Paul et al. 2014). It should be noted that while glucoronide conjugates of (R,S)-Ket metabolites have been identified in plasma samples obtained from patients receiving (R,S)-Ket for the treatment of Complex Regional Pain Syndrome (Moaddel et al. 2010) the samples obtained in this study were not assayed for these compounds. The measured plasma concentrations of (2S,6S)-HNK at 10, 20, and 60 min after i.v. administration of (2S,6S)-HNK are presented in Table1 and the plasma concentration–time curves following i.v. and p.o. administration are presented in Figure2.


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)

Plasma profile of (2S, 6S)-6-hydroxynorketamine administered i.v. and po routes, 20 mg/kg to male wistar rats. Each data point represents the mean ± SD for n = 3 rats. Time points were collected through 72 h, but drug was not detected in plasma samples from the final time point.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: Plasma profile of (2S, 6S)-6-hydroxynorketamine administered i.v. and po routes, 20 mg/kg to male wistar rats. Each data point represents the mean ± SD for n = 3 rats. Time points were collected through 72 h, but drug was not detected in plasma samples from the final time point.
Mentions: The only compound identified in the analysis of the plasma samples obtained after the i.v. and p.o. administration of (2S,6S)-HNK was the administered (2S,6S)-HNK (data not shown). This is consistent with the data from previous studies in the rat in which the administration of (2S,6S;2R,6R)-HNK and (2S,6S)-HNK resulted in no additional Phase I metabolites or chiral inversion of an asymmetric center (Leung and Baillie 1986; Paul et al. 2014). It should be noted that while glucoronide conjugates of (R,S)-Ket metabolites have been identified in plasma samples obtained from patients receiving (R,S)-Ket for the treatment of Complex Regional Pain Syndrome (Moaddel et al. 2010) the samples obtained in this study were not assayed for these compounds. The measured plasma concentrations of (2S,6S)-HNK at 10, 20, and 60 min after i.v. administration of (2S,6S)-HNK are presented in Table1 and the plasma concentration–time curves following i.v. and p.o. administration are presented in Figure2.

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.