Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity

Persson, Jan; Hasselström, Jan; Maurset, A; I, Oye; Svensson, Jan‐Olof; Almqvist, Ove; Scheinin, Harry; Gustafsson, Lars L.

doi:10.1007/s002280100353

Cited by 63 publications

(51 citation statements)

References 27 publications

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“…In vivo studies in humans have shown higher values for the clearance of S-ket than for R-ket either after administration of the individual enantiomers (Persson et al, 2002;White et al, 1985) or after administration of the racemic mixture (Henthorn et al, 1999;Geisslinger et al, 1993;Ihmsen et al, 2001). Our results also clearly show differences in biotransformation of ketamine and/or norketamine enantiomers resulting in consistently higher plasma concentrations of S-nor than of R-nor.…”

Section: Discussion Pharmacokineticssupporting

confidence: 57%

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 Pharmacokineticssupporting

confidence: 57%

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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“…The pathways involved in the metabolism of ketamine have been of interest particularly in view of the pronounced polymorphisms of enzymes such as CYP2D6 and CYP2C19 [22]. Updates, primarily on animal and in-vitro data, identify CYP2B6, CYP3A4 and to a lesser extent CYP2C9 as the main enzymes metabolizing ketamine [26,27].…”

Section: Enantiomersmentioning

confidence: 98%

“…It has been well established that the elimination clearance of S-ketamine is larger than that of R-ketamine. The volume of distribution of the central compartment and at steady state might also be larger [22]. The S-form has been commercially available for several years, probably based on the perception that it would have a better effect to side-effect ratio [23].…”

Section: Enantiomersmentioning

confidence: 99%

Wherefore ketamine?

Persson

2010

Current Opinion in Anaesthesiology

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“…The patients were shown to have reduced metabolic capacity on the basis of phenotype data using the oxidative pathways of model substrates debrisoquin (CYP2D6) and mephenytoin (CYP2C19) (Persson et al, 2002). Based on the data gathered in this study, it was shown that pharmacokinetics of individual enantiomers of ketamine in normal subjects and subjects with impaired CYP isozymes were similar.…”

Section: Ketaminementioning

confidence: 97%

“…Based on the data gathered in this study, it was shown that pharmacokinetics of individual enantiomers of ketamine in normal subjects and subjects with impaired CYP isozymes were similar. Interestingly, the arterial kinetic parameters (volume of distribution; MRT) for the two enantiomers of ketamine showed differences when compared with the intravenous kinetic parameters (Persson et al, 2002).…”

Section: Ketaminementioning

confidence: 99%

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

Srinivas

2006

Biomedical Chromatography

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The concepts of drug development have evolved over the last few decades. Although number of novel chemical entitities belonging to varied classes have made it to the market, the process of drug development is challenging, intertwined as it is with complexities and uncertainities. The intention of this article is to provide a comprehensive review of novel chemical entities (NCEs) that are substrates to cytochrome P450 (CYP) 2D6 isozyme. Topics covered in this review aim: (1) to provide a framework of the importance of CYP2D6 isozyme in the biotransformation of NCEs as stand-alones and/or in conjunction with other CYP isozymes; (2) to provide several case studies of drug disposition of important drug substrates, (3) to cover key analytical perspectives and key assay considerations to assess the role and involvement of CYP2D6, and (4) to elaborate some important considerations from the development point of view. Additionally, wherever applicable, special emphasis is provided on chiral drug substrates in the various subsections of the review.

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Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity

Cited by 63 publications

References 27 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

Wherefore ketamine?

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

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