Metabolism of Ketamine Stereoisomers by Human Liver Microsomes

Kharasch, Evan D.; Labroo, Rita

doi:10.1097/00000542-199212000-00022

Cited by 122 publications

(81 citation statements)

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“…Ihmsen et al (2001) reported that the clearance of S-ket, when administered as pure enantiomer, was significantly larger than the clearance of S-ket when administered in the racemate. They suggested an inhibition of the metabolism of S-ket by R-ket referring to an in vitro study of Kharasch and Labroo (1992). Using human liver microsomes, the rate of N-demethylation of the racemate was found to be significantly smaller than the sum of the rates of the individual enantiomers.…”

Section: Discussion Pharmacokineticsmentioning

confidence: 99%

Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion

Knobloch

Portier

Levionnois

et al. 2006

Toxicology and Applied Pharmacology

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Ketamine is widely used as an anesthetic in a variety of drug combinations in human and veterinary medicine. Recently, it gained new interest for use in long-term pain therapy administered in subanesthetic doses in humans and animals. The purpose of this study was to develop a physiologically based pharmacokinetic (PBPk) model for ketamine in ponies and to investigate the effect of lowdose ketamine infusion on the amplitude and the duration of the nociceptive withdrawal reflex (NWR).A target-controlled infusion (TCI) of ketamine with a target plasma level of 1 μg/ml S-ketamine over 120 min under isoflurane anesthesia was performed in Shetland ponies. A quantitative electromyographic assessment of the NWR was done before, during and after the TCI. Plasma levels of R-/S-ketamine and R-/S-norketamine were determined by enantioselective capillary electrophoresis. These data and two additional data sets from bolus studies were used to build a PBPk model for ketamine in ponies.The peak-to-peak amplitude and the duration of the NWR decreased significantly during TCI and returned slowly toward baseline values after the end of TCI. The PBPk model provides reliable prediction of plasma and tissue levels of R-and S-ketamine and R-and S-norketamine. Furthermore, biotransformation of ketamine takes place in the liver and in the lung via first-pass metabolism. Plasma concentrations of S-norketamine were higher compared to R-norketamine during TCI at all time points. Analysis of the data suggested identical biotransformation rates from the parent compounds to the principle metabolites (R-and S-norketamine) but different downstream metabolism to further metabolites. The PBPk model can provide predictions of R-and S-ketamine and norketamine concentrations in other clinical settings (e.g. horses).

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Section: Discussion Pharmacokineticsmentioning

confidence: 99%

Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion

Knobloch

Portier

Levionnois

et al. 2006

Toxicology and Applied Pharmacology

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“…Pharmacokinetic parameters for ketamine were taken from a previous study (Domino et al 1984). The target concentrations were designed to approximate the range of concentrations hypothetically achieved by the low and high doses infused in the Krystal et al (1994) and Malhotra et al (1996) studies; the total dose of ketamine infused was 0.97 mg/kg over 2 h. Ketamine plasma concentrations were determined by gas chromatography mass spectrometry (Kharasch and Labroo 1992).…”

Section: Protocolmentioning

confidence: 99%

Does Ketamine-Mediated N-methyl-D-aspartate Receptor Antagonism Cause Schizophrenia-like Oculomotor Abnormalities?

Radant

Bowdle

Cowley

et al. 1998

Neuropsychopharmacology

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“…1). It is typically administered as racemate although S-ketamine is more potent than R-ketamine and exhibits a greater clearance and faster anesthetic recovery compared with the racemate [1][2][3][4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

CE provides evidence of the stereoselective hydroxylation of norketamine in equines

et al. 2009

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CE provides evidence of the stereoselective hydroxylation of norketamine in equinesCE with multiple isomer sulfated-CD as selector was used for the simultaneous analysis of the stereoisomers of ketamine, norketamine, 5,6-dehydronorketamine and hydroxylated metabolites of norketamine in liquid/liquid extracts of (i) in vitro incubations with ketamine or norketamine and equine liver microsomes and (ii) plasma and urine of ponies receiving a target-controlled infusion of ketamine under isoflurane anesthesia. Hydroxynorketamine metabolites with the hydroxy group at the cyclohexanone ring could be shown to be formed stereoselectively both in vitro and in vivo. Due to the lack of standard compounds, urinary extracts were fractionated by HPLC followed by characterization of the collected fractions with CE and LC-MS n with 0.7 mmu mass discrimination. Comparison of LC-MS n data obtained with the fractions, an in vitro microsomal sample, and both pony urine and hydrolyzed pony urine led to the identification of four hydroxylated norketamine metabolites with hydroxylation at the cyclohexanone ring, two with hydroxylation at the aromatic ring and four hydroxylated metabolites of ketamine. Due to the lower detection sensitivity, only the four hydroxynorketamine metabolites with hydroxylation at the cyclohexanone ring were observed by CE. The data suggest that demethylation of ketamine followed by hydroxylation of norketamine at the cyclohexanone ring is the major metabolic pathway in equine species and that the ketamine metabolism is highly stereoselective.

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Metabolism of Ketamine Stereoisomers by Human Liver Microsomes

Cited by 122 publications

References 0 publications

Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion

Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion

Does Ketamine-Mediated N-methyl-D-aspartate Receptor Antagonism Cause Schizophrenia-like Oculomotor Abnormalities?

CE provides evidence of the stereoselective hydroxylation of norketamine in equines

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