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Research ArticleArticle

The CYP2B6*6 Allele Significantly Alters the N-Demethylation of Ketamine Enantiomers In Vitro

Yibai Li, Janet K. Coller, Mark R. Hutchinson, Kathrin Klein, Ulrich M. Zanger, Nathan J. Stanley, Andrew D. Abell and Andrew A. Somogyi
Drug Metabolism and Disposition June 2013, 41 (6) 1264-1272; DOI: https://doi.org/10.1124/dmd.113.051631
Yibai Li
Discipline of Pharmacology (Y.L., J.K.C., A.A.S.), Discipline of Physiology (M.R.H.), Discipline of Chemistry (A.D.A.), and Centre for Personalised Cancer Medicine (A.A.S.), The University of Adelaide, Adelaide, South Australia, Australia; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.); and Department of Chemistry, University of Otago, Dunedin, New Zealand (N.J.S.)
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Janet K. Coller
Discipline of Pharmacology (Y.L., J.K.C., A.A.S.), Discipline of Physiology (M.R.H.), Discipline of Chemistry (A.D.A.), and Centre for Personalised Cancer Medicine (A.A.S.), The University of Adelaide, Adelaide, South Australia, Australia; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.); and Department of Chemistry, University of Otago, Dunedin, New Zealand (N.J.S.)
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Mark R. Hutchinson
Discipline of Pharmacology (Y.L., J.K.C., A.A.S.), Discipline of Physiology (M.R.H.), Discipline of Chemistry (A.D.A.), and Centre for Personalised Cancer Medicine (A.A.S.), The University of Adelaide, Adelaide, South Australia, Australia; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.); and Department of Chemistry, University of Otago, Dunedin, New Zealand (N.J.S.)
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Kathrin Klein
Discipline of Pharmacology (Y.L., J.K.C., A.A.S.), Discipline of Physiology (M.R.H.), Discipline of Chemistry (A.D.A.), and Centre for Personalised Cancer Medicine (A.A.S.), The University of Adelaide, Adelaide, South Australia, Australia; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.); and Department of Chemistry, University of Otago, Dunedin, New Zealand (N.J.S.)
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Ulrich M. Zanger
Discipline of Pharmacology (Y.L., J.K.C., A.A.S.), Discipline of Physiology (M.R.H.), Discipline of Chemistry (A.D.A.), and Centre for Personalised Cancer Medicine (A.A.S.), The University of Adelaide, Adelaide, South Australia, Australia; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.); and Department of Chemistry, University of Otago, Dunedin, New Zealand (N.J.S.)
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Nathan J. Stanley
Discipline of Pharmacology (Y.L., J.K.C., A.A.S.), Discipline of Physiology (M.R.H.), Discipline of Chemistry (A.D.A.), and Centre for Personalised Cancer Medicine (A.A.S.), The University of Adelaide, Adelaide, South Australia, Australia; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.); and Department of Chemistry, University of Otago, Dunedin, New Zealand (N.J.S.)
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Andrew D. Abell
Discipline of Pharmacology (Y.L., J.K.C., A.A.S.), Discipline of Physiology (M.R.H.), Discipline of Chemistry (A.D.A.), and Centre for Personalised Cancer Medicine (A.A.S.), The University of Adelaide, Adelaide, South Australia, Australia; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.); and Department of Chemistry, University of Otago, Dunedin, New Zealand (N.J.S.)
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Andrew A. Somogyi
Discipline of Pharmacology (Y.L., J.K.C., A.A.S.), Discipline of Physiology (M.R.H.), Discipline of Chemistry (A.D.A.), and Centre for Personalised Cancer Medicine (A.A.S.), The University of Adelaide, Adelaide, South Australia, Australia; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.); and Department of Chemistry, University of Otago, Dunedin, New Zealand (N.J.S.)
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Abstract

Ketamine is primarily metabolized to norketamine by hepatic CYP2B6 and CYP3A4-mediated N-demethylation. However, the relative contribution from each enzyme remains controversial. The CYP2B6*6 allele is associated with reduced enzyme expression and activity that may lead to interindividual variability in ketamine metabolism. We examined the N-demethylation of individual ketamine enantiomers using human liver microsomes (HLMs) genotyped for the CYP2B6*6 allele, insect cell–expressed recombinant CYP2B6 and CYP3A4 enzymes, and COS-1 cell–expressed recombinant CYP2B6.1 and CYP2B6.6 protein variant. Effects of CYP-selective inhibitors on norketamine formation were also determined in HLMs. The two-enzyme Michaelis-Menten model best fitted the HLM kinetic data. The Michaelis-Menten constants (Km) for the high-affinity enzyme and the low-affinity enzyme were similar to those for the expressed CYP2B6 and CYP3A4, respectively. The intrinsic clearance for both ketamine enantiomers by the high-affinity enzyme in HLMs with CYP2B6*1/*1 genotype were at least 2-fold and 6-fold higher, respectively, than those for CYP2B6*1/*6 genotype and CYP2B6*6/*6 genotype. The Vmax and Km values for CYP2B6.1 were approximately 160 and 70% of those for CYP2B6.6, respectively. N,N′N′-triethylenethiophosphoramide (thioTEPA) (CYP2B6 inhibitor, 25 μM) and the monoclonal antibody against CYP2B6 but not troleandomycin (CYP3A4 inhibitor, 25 μM) or the monoclonal antibody against CYP3A4 inhibited ketamine N-demethylation at clinically relevant concentrations. The degree of inhibition was significantly reduced in HLMs with the CYP2B6*6 allele (gene-dose P < 0.05). These results indicate a major role of CYP2B6 in ketamine N-demethylation in vitro and a significant impact of the CYP2B6*6 allele on enzyme-ketamine binding and catalytic activity.

Footnotes

    • Received February 25, 2013.
    • Accepted April 2, 2013.
  • This work was supported by University of Adelaide, School of Medical Sciences funding, Adelaide Graduate Fee Scholarship; the Australian Research Council Australian Research Fellowship [Grant DP110100297]; FTT Fricker Research Fellowship [Medical Endowment Funds, University of Adelaide]; and the Robert Bosch Foundation, Stuttgart, Germany.

  • This work was previously presented at the following conferences: Somogyi AA (2012) Impact of CYP2B6*6 genotype on ketamine human pharmacokinetics and microsomal metabolism. 19th International Symposium on Microsomes and Drug Oxidations and 12th European ISSX Meeting; 2012 June 17–21; Noordwijk aan Zee, The Netherlands; and Li Y (2012) CYP2B6*6 mutation significantly reduces in vitro N-demethylation of ketamine enantiomers. Joint ASCEPT-APSA 2012 Conference; 2012 December 2–5; Sydney, NSW, Australia.

  • dx.doi.org/10.1124/dmd.113.051631.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (6)
Drug Metabolism and Disposition
Vol. 41, Issue 6
1 Jun 2013
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Research ArticleArticle

CYP2B6*6 and Ketamine Metabolism

Yibai Li, Janet K. Coller, Mark R. Hutchinson, Kathrin Klein, Ulrich M. Zanger, Nathan J. Stanley, Andrew D. Abell and Andrew A. Somogyi
Drug Metabolism and Disposition June 1, 2013, 41 (6) 1264-1272; DOI: https://doi.org/10.1124/dmd.113.051631

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Research ArticleArticle

CYP2B6*6 and Ketamine Metabolism

Yibai Li, Janet K. Coller, Mark R. Hutchinson, Kathrin Klein, Ulrich M. Zanger, Nathan J. Stanley, Andrew D. Abell and Andrew A. Somogyi
Drug Metabolism and Disposition June 1, 2013, 41 (6) 1264-1272; DOI: https://doi.org/10.1124/dmd.113.051631
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