TY - JOUR T1 - The <em>CYP2B6*6</em> Allele Significantly Alters the <em>N-</em>Demethylation of Ketamine Enantiomers In Vitro JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1264 LP - 1272 DO - 10.1124/dmd.113.051631 VL - 41 IS - 6 AU - Yibai Li AU - Janet K. Coller AU - Mark R. Hutchinson AU - Kathrin Klein AU - Ulrich M. Zanger AU - Nathan J. Stanley AU - Andrew D. Abell AU - Andrew A. Somogyi Y1 - 2013/06/01 UR - http://dmd.aspetjournals.org/content/41/6/1264.abstract N2 - 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 &lt; 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. ER -