| Autor: |
Li, Yibai, Coller, Janet K., Hutchinson, Mark R., Klein, Kathrin, Zanger, Ulrich M., Stanley, Nathan J., Abell, Andrew D., Somogyi, Andrew A. |
| Zdroj: |
Drug Metabolism and Disposition; June 2013, Vol. 41 Issue: 6 p1264-1272, 9p |
| Abstrakt: |
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*6allele 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*6allele, 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/*1genotype were at least 2-fold and 6-fold higher, respectively, than those for CYP2B6*1/*6genotype and CYP2B6*6/*6genotype. The Vmaxand Kmvalues 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*6allele (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*6allele on enzyme-ketamine binding and catalytic activity. |
| Databáze: |
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