Characterization of the stereoselective biotransformation of ketamine to norketaminevia determination of their enantiomers in equine plasma by capillary electrophoresis

Theurillat, Regula; Knobloch, Monika; Levionnois, Olivier; Larenza, Paula M; Mevissen, Meike; Thormann, Wolfgang

doi:10.1002/elps.200500059

Cited by 38 publications

(49 citation statements)

References 21 publications

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“…Thus, Table 1 shows the use of LLE for the determination of drugs in biological samples as plasma [20][21][22][23], human serum [17,19], human urine [17], and a microsomal fraction of liver homogenates [18]. Preconcentration factors up to 21 were achieved by this extraction procedure.…”

Section: Off-line Sample Treatment Techniques In Sensitive Chiral Anamentioning

confidence: 99%

“…Preconcentration factors up to 21 were achieved by this extraction procedure. After this sample treatment step, LODs from 10 26 to 3610 28 M were reported when UV detection was used [17][18][19][20] and LODs ranging form 3610 26 to 4610 29 M were reached with ESI-MS detection [21,22]. As example, Schappler et al [22] assessed two approaches to enhance the sensitivity in CE.…”

Section: Off-line Sample Treatment Techniques In Sensitive Chiral Anamentioning

confidence: 99%

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Sensitive chiral analysis by CE: An update

et al. 2007

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Sensitive chiral analysis by CE: An updateA general view of the different strategies used in the last years to enhance the detection sensitivity in chiral analysis by CE is provided in this article. With this purpose and in order to update the previous review by García-Ruiz et al., the articles appeared on this subject from January 2005 to March 2007 are considered. Three were the main strategies employed to increase the detection sensitivity in chiral analysis by CE: (i) the use of off-line sample treatment techniques, (ii) the employment of in-capillary preconcentration techniques based on electrophoretic principles, and (iii) the use of alternative detection systems to the widely employed on-column UV-Vis absorption detection. Combinations of two or three of the above-mentioned strategies gave rise to adequate concentration detection limits up to 10 210 M enabling enantiomer analysis in a variety of real samples including complex biological matrices.

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Section: Off-line Sample Treatment Techniques In Sensitive Chiral Anamentioning

confidence: 99%

Section: Off-line Sample Treatment Techniques In Sensitive Chiral Anamentioning

confidence: 99%

Sensitive chiral analysis by CE: An update

et al. 2007

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“…Enantiomers of ketamine and its active metabolite norketamine were measured in plasma using capillary electrophoresis (Theurillat et al, 2005). Briefly, the assay is based upon liquid-liquid extraction of ketamine and norketamine from 1 ml plasma followed by analysis of the reconstituted extract by capillary electrophoresis in the presence of a phosphate buffer (pH 2.5) containing 10 mg/ml highly sulfated β-cyclodextrin 5 as a chiral selector.…”

Section: Enantioselective Analysis Of Ketamine and Norketamine In Plasmamentioning

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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“…Thus, interdisciplinary research efforts are undertaken to assess the use of ketamine (as racemic mixture) versus S-ketamine for anesthesia and pain therapy in horses. This work required the development of stereoselective assays for a variety of applications [25][26][27][28][29][30][31]. Enantioselective CE assays were found to be attractive approaches for the assessment of the stereoselectivity of drug metabolism [32][33][34].…”

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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Characterization of the stereoselective biotransformation of ketamine to norketaminevia determination of their enantiomers in equine plasma by capillary electrophoresis

Cited by 38 publications

References 21 publications

Sensitive chiral analysis by CE: An update

Sensitive chiral analysis by CE: An update

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

CE provides evidence of the stereoselective hydroxylation of norketamine in equines

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