Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/78366
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Type: Journal article
Title: The CYP2B6*6 allele significantly alters the N-demethylation of ketamine enantiomers in vitro
Author: Li, Y.
Coller, J.
Hutchinson, M.
Klein, K.
Zanger, U.
Stanley, N.
Abell, A.
Somogyi, A.
Citation: Drug Metabolism and Disposition, 2013; 41(6):1264-1272
Publisher: Amer Soc Pharmacology Experimental Therapeutics
Issue Date: 2013
ISSN: 0090-9556
1521-009X
Statement of
Responsibility: 
Yibai Li, Janet K. Coller, Mark R. Hutchinson, Kathrin Klein, Ulrich M. Zanger, Nathan J. Stanley, Andrew D. Abell, and Andrew A. Somogyi
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 (K(m)) 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 V(max) and K(m) 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.
Keywords: COS Cells; Animals; Cercopithecus aethiops; Humans; Insects; Ketamine; Aryl Hydrocarbon Hydroxylases; DNA Methylation; Alleles; Stereoisomerism; Adult; Aged; Middle Aged; Female; Male; Cytochrome P-450 CYP3A
Rights: Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
RMID: 0020128792
DOI: 10.1124/dmd.113.051631
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