Effects of Protein Calorie Malnutrition on the Pharmacokinetics of Ketamine in Rats

Williams, Monique; Mager, Donald E.; Parenteau, Heli; Gudi, Girish; Tracy, Timothy S.; Mulheran, M.; Wainer, Irving W.

doi:10.1124/dmd.32.8.786

Cited by 30 publications

(27 citation statements)

References 29 publications

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“…2C (first peak shown only, marked with asterisk), 4B (peaks marked with asterisks)). Based on the work of Wainer et al [4,13], one could assume that these are the peaks for S-and R-dehydronorketamine. Further evidence is given by the fact that …”

Section: Analysis Of Ketamine and Norketamine Enantiomers In Plasma Ementioning

confidence: 99%

“…As of today, ketamine and norketamine enantiomers in human and animal plasma have mainly been determined by HPLC using expensive, enantioselective columns that are based upon immobilized a 1 -acid glycoprotein (AGP) [8][9][10][11] or cellulose tris(3,5-dimethylphenylcarbamate)-coated silica-gel (Chiralcel OD) [12]. An enantioselective GC method that features a b-CD-based chiral stationary phase has also been reported [13].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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A robust CE method for the simultaneous determination of the enantiomers of ketamine and norketamine in equine plasma is described. It is based upon liquid-liquid extraction of ketamine and norketamine at alkaline pH from 1 mL plasma followed by analysis of the reconstituted extract by CE in the presence of a pH 2.5 Tris-phosphate buffer containing 10 mg/mL highly sulfated beta-CD as chiral selector. Enantiomer plasma levels between 0.04 and 2.5 microg/mL are shown to provide linear calibration graphs. Intraday and interday precisions evaluated from peak area ratios (n = 5) at the lowest calibrator concentration are < 8 and < 14%, respectively. The LOD for all enantiomers is 0.01 microg/mL. After i.v. bolus administration of 2.2 mg/kg racemic ketamine, the assay is demonstrated to provide reliable data for plasma samples of ponies under isoflurane anesthesia, of ponies premedicated with xylazine, and of one horse that received romifidine, L-methadone, guaifenisine, and isoflurane. In animals not premedicated with xylazine, the ketamine N-demethylation is demonstrated to be enantioselective. The concentrations of the two ketamine enantiomers in plasma are equal whereas S-norketamine is found in a larger amount than R-norketamine. In the group receiving xylazine, data obtained do not reveal this stereoselectivity.

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Section: Analysis Of Ketamine and Norketamine Enantiomers In Plasma Ementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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“…2012), however, to date only one study presented a pharmacokinetic model for the enantiomers of (R,S)-DHNK in the rat model (Williams et al. 2004). …”

Section: Introductionmentioning

confidence: 99%

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

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Sanghvi

Dossou

et al. 2015

Pharmacology Res & Perspec

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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 (t1/2) was 8.0 ± 4.0 h and the apparent volume of distribution (Vd) 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.

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“…Most assays for ketamine and metabolites in biosamples are based on chromatographic techniques [9][10][11][12], including those for enantioselective resolution [13][14][15][16][17][18], and are targeted to ketamine, norketamine and in certain cases also 5,6-dehydronorketamine. Only a few studies are available reporting the determination of hydroxylated ketamine and norketamine metabolites in biosamples.…”

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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Effects of Protein Calorie Malnutrition on the Pharmacokinetics of Ketamine in Rats

Cited by 30 publications

References 29 publications

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

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

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

CE provides evidence of the stereoselective hydroxylation of norketamine in equines

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