Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance

  title={Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance},
  author={Lesley K Rao and Alicia M Flaker and Christina Friedel and Evan D. Kharasch},
Background:At therapeutic concentrations, cytochrome P4502B6 (CYP2B6) is the major P450 isoform catalyzing hepatic ketamine N-demethylation to norketamine in vitro. The CYP2B6 gene is highly polymorphic. The most common variant allele, CYP2B6*6, is associated with diminished hepatic CYP2B6 expression and catalytic activity compared with wild-type CYP2B6*1/*1. CYP2B6.6, the protein encoded by the CYP2B6*6 allele, and liver microsomes from CYP2B6*6 carriers had diminished ketamine metabolism in… 
Stereoselective Ketamine Metabolism by Genetic Variants of Cytochrome P450 CYP2B6 and Cytochrome P450 Oxidoreductase
Genetic variants of CYP2B6 and P450 oxidoreductase have diminished ketamine N-demethylation activity, without affecting the stereoselectivity of metabolism.
Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition
Clinical hydroxylation of both bupropion enantiomers was equivalently influenced by CYP2B6 allelic variation, which may affect therapeutic outcomes.
Nicotine oxidation by genetic variants of CYP2B6 and in human brain microsomes
It is concluded that CYP2B6 metabolizes nicotine stereoselectively and common CYP 2B6 variants differ in nicotine metabolism activity, but did not find evidence of CYP1B6 activity in human brain.
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The authors present their work on the pharmacogenetics of ketamine in an attempt to better understand the etiologies of drug response variability, beginning with metabolism and pharmacokinetic differences and offer several plausible explanations invoking dose, route of drug administration, and population characteristics.
Chiral Pharmacokinetics and Metabolite Profile of Prolonged-release Ketamine Tablets in Healthy Human Subjects
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The CYP2B6*6 Allele Significantly Alters the N-Demethylation of Ketamine Enantiomers In Vitro
Results indicate a major role of CYP2B6 in ketamine N-demethylation in vitro and a significant impact of the CYP 2B6*6 allele on enzyme-ketamine binding and catalytic activity.
Methadone Pharmacogenetics: CYP2B6 Polymorphisms Determine Plasma Concentrations, Clearance, and Metabolism
Methadone metabolism and clearance were lower in African Americans in part because of the CYP2B6*6 genetic polymorphism, and subjects at risk for methadone toxicity and drug interactions were identified.
Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance
Recent advances on the functional and clinical significance of CYP2B6 and its genetic polymorphism are summarized, with particular emphasis on the comparison of kinetic data obtained with different substrates for variants expressed in different recombinant expression systems.
Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes.
  • Y. Hijazi, R. Boulieu
  • Biology, Chemistry
    Drug metabolism and disposition: the biological fate of chemicals
  • 2002
It is demonstrated that CYP3A4 is the principal enzyme responsible for ketamine N-demethylation in human liver microsomes and that CYB2B6 and CYP2C9 have a minor contribution to ketamines N- Demethylation at therapeutic concentrations of the drug.
CYP2B6*6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: impact on adverse effects.
The CYP2B6*6 allele is associated with a substantial decrease in steady-state ketamine plasma clearance in chronic pain patients and the decreased clearance and resultant higher plasma concentrations may beassociated with a higher incidence of ketamine adverse effects.
Ketamine as a probe for medetomidine stereoisomer inhibition of human liver microsomal drug metabolism.
Spectral studies showed that DMED interacted with microsomal cytochrome P-450 to elicit a Type II binding spectrum, and LMED, although pharmacologically inactive, had a greater inhibitory effect than DMED on racemic ketamine and ketamine enantiomer demethylation at therapeutic concentrations.
Metabolism of ketamine stereoisomers by human liver microsomes.
To characterize ketamine racemate and enantiomer metabolism by human liver and to test the hypothesis that differences in hepatic ketamine enantiomers metabolism can account for observed differences in ketamineEnantiomer pharmacokinetics, it is found that S(+) ketamine exhibits a greater clearance and faster anesthetic recovery compared to the racemate.
Rifampicin has a Profound Effect on the Pharmacokinetics of Oral S‐Ketamine and Less on Intravenous S‐Ketamine
Rifampicin profoundly reduces the plasma concentrations of ketamine and norketamine after oral administration of S‐ketamine, by inducing mainly its first‐pass metabolism.