Fundamental #13: Note changes in health over time
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Yanagihara Y, Kariya S, Ohtani M, Uchino K, Aoyama T, Yamamura Y, Iga T. 
“Involvement of CYP2B6 in n-demethylation of ketamine in human liver microsomes”. 
Drug Metab Dispos. 2001 Jun 16;29(6):887-90.
Abstract
Ketamine is metabolized by cytochrome P450 CYP leading to production of pharmacologically active products and contributing to drug excretion. We identified the CYP enzymes involved in the N-demethylation of ketamine enantiomers using pooled human liver microsomes and microsomes from human B-lymphoblastoid cells that expressed CYP enzymes. The kinetic data in human liver microsomes for the R- and S-ketamine N-demethylase activities could be analyzed as two-enzyme systems. The Km values were 31 and 496 microM for R-ketamine, and 24 and 444 microM for S-ketamine. Among the 12 cDNA-expressed CYP enzymes examined, CYP2B6, CYP2C9, and CYP3A4 showed high activities for the N-demethylation of both enantiomers at the substrate concentration of 1 mM. CYP2B6 had the lowest Km value for the N-demethylation of R- and S-ketamine 74 and 44 microM, respectively. Also, the intrinsic clearance CLint: Vmax/Km of CYP2B6 for the N-demethylation of both enantiomers were 7 to 13 times higher than those of CYP2C9 and CYP3A4. Orphenadrine CYP2B6 inhibitor, 500 microM and sulfaphenazole CYP2C9 inhibitor, 100 microM inhibited the N-demethylase activities for both enantiomers 5 microM in human liver microsomes by 60 to 70, whereas cyclosporin A CYP3A4 inhibitor, 100 microM failed to inhibit these activities. In addition, the anti-CYP2B6 antibody inhibited these activities in human liver microsomes by 80, whereas anti-CYP2C antibody and anti-CYP3A4 antibody failed to inhibit these activities. These results suggest that the high affinity/low capacity enzyme in human liver microsomes is mediated by CYP2B6, and the low affinity/high capacity enzyme is mediated by CYP2C9 and CYP3A4. CYP2B6 mainly mediates the N-demethylation of R- and S-ketamine in human liver microsomes at therapeutic concentrations 5 microM.
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