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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.


The chromatographic trace from the achiral analysis of a plasma sample obtained 10 min after administration of a 20 mg/kg dose of (S)-Ket (A) and 20 mg/kg of (R)- Ket (B), where 1 = Ket, 2 = norKet, 3 = DHNK, and 4 = HNK.
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fig01: The chromatographic trace from the achiral analysis of a plasma sample obtained 10 min after administration of a 20 mg/kg dose of (S)-Ket (A) and 20 mg/kg of (R)- Ket (B), where 1 = Ket, 2 = norKet, 3 = DHNK, and 4 = HNK.

Mentions: After i.v. administration of 20 mg/kg (S)-Ket, the parent drug and five of the eight major metabolites, see Scheme 3, were present at quantitative levels in plasma 10 min after dosing, Figure1A, Table1. The results indicate that (S)-Ket was rapidly transformed into (2S,6S)-HNK and that the circulating concentration of this metabolite exceeded the parent compound at 20 and 60 min post administration, Table1. In comparison, the chromatogram obtained 10 min after the i.v. administration of 20 mg/kg (R)-Ket demonstrated that quantifiable concentrations of the parent drug and seven of the eight potential metabolites (Scheme 3) were present in the plasma sample, Figure1B, Table1. However, unlike the data obtained after the administration of (S)-Ket, the plasma concentrations of (2R,6R)-HNK did not exceed those of (R)-Ket in the samples collected during the first 60 min after dosing, Table1. The data indicate that (S)-Ket is a more efficient source of the (2,6)-HNK metabolite as the plasma concentrations of (2S,6S)-HNK were significantly higher than (2R,6R)-HNK (P < 0.005) at the 10, 20, and 60 min sampling times. It is of interest to note that there appears to be no significant enantioselectivity in the metabolic route depicted by Pathway B in Scheme 3, which is another source of the (2,6)-HNK metabolites. While (2S,6S)-HNK and (2R,6R)-HNK are products of Pathways A and B, (2S,6R)-HNK, and (2R,6S)-HNK are only produced by Pathway B (Desta et al. 2012; Paul et al. 2014). This was confirmed in this study, where the (2S,6R;2R,6S) was not detected after the i.v. administration of (R,S)-norKet (data not shown). There were no significant differences in the plasma concentrations of (2S,6R)-HNK and (2R,6S)-HNK during the first 60 min post administration of (S)-Ket and (R)- Ket, Table1.


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)

The chromatographic trace from the achiral analysis of a plasma sample obtained 10 min after administration of a 20 mg/kg dose of (S)-Ket (A) and 20 mg/kg of (R)- Ket (B), where 1 = Ket, 2 = norKet, 3 = DHNK, and 4 = HNK.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: The chromatographic trace from the achiral analysis of a plasma sample obtained 10 min after administration of a 20 mg/kg dose of (S)-Ket (A) and 20 mg/kg of (R)- Ket (B), where 1 = Ket, 2 = norKet, 3 = DHNK, and 4 = HNK.
Mentions: After i.v. administration of 20 mg/kg (S)-Ket, the parent drug and five of the eight major metabolites, see Scheme 3, were present at quantitative levels in plasma 10 min after dosing, Figure1A, Table1. The results indicate that (S)-Ket was rapidly transformed into (2S,6S)-HNK and that the circulating concentration of this metabolite exceeded the parent compound at 20 and 60 min post administration, Table1. In comparison, the chromatogram obtained 10 min after the i.v. administration of 20 mg/kg (R)-Ket demonstrated that quantifiable concentrations of the parent drug and seven of the eight potential metabolites (Scheme 3) were present in the plasma sample, Figure1B, Table1. However, unlike the data obtained after the administration of (S)-Ket, the plasma concentrations of (2R,6R)-HNK did not exceed those of (R)-Ket in the samples collected during the first 60 min after dosing, Table1. The data indicate that (S)-Ket is a more efficient source of the (2,6)-HNK metabolite as the plasma concentrations of (2S,6S)-HNK were significantly higher than (2R,6R)-HNK (P < 0.005) at the 10, 20, and 60 min sampling times. It is of interest to note that there appears to be no significant enantioselectivity in the metabolic route depicted by Pathway B in Scheme 3, which is another source of the (2,6)-HNK metabolites. While (2S,6S)-HNK and (2R,6R)-HNK are products of Pathways A and B, (2S,6R)-HNK, and (2R,6S)-HNK are only produced by Pathway B (Desta et al. 2012; Paul et al. 2014). This was confirmed in this study, where the (2S,6R;2R,6S) was not detected after the i.v. administration of (R,S)-norKet (data not shown). There were no significant differences in the plasma concentrations of (2S,6R)-HNK and (2R,6S)-HNK during the first 60 min post administration of (S)-Ket and (R)- Ket, Table1.

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.