RT Journal Article
SR Electronic
T1 Involvement of CYP2B6 in <em>N</em>-Demethylation of Ketamine in Human Liver Microsomes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 887
OP 890
VO 29
IS 6
A1 Yoshitsugu Yanagihara
A1 Satoru Kariya
A1 Michiteru Ohtani
A1 Katsuyoshi Uchino
A1 Takao Aoyama
A1 Yoshikazu Yamamura
A1 Tatsuji Iga
YR 2001
UL http://dmd.aspetjournals.org/content/29/6/887.abstract
AB 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 theN-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)-ketamineN-demethylase activities could be analyzed as two-enzyme systems. The K m values were 31 and 496 μM for (R)-ketamine, and 24 and 444 μM for (S)-ketamine. Among the 12 cDNA-expressed CYP enzymes examined, CYP2B6, CYP2C9, and CYP3A4 showed high activities for theN-demethylation of both enantiomers at the substrate concentration of 1 mM. CYP2B6 had the lowestK m value for theN-demethylation of (R)- and (S)-ketamine (74 and 44 μM, respectively). Also, the intrinsic clearance (CLint:V max/K m) 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 μM) and sulfaphenazole (CYP2C9 inhibitor, 100 μM) inhibited the N-demethylase activities for both enantiomers (5 μM) in human liver microsomes by 60 to 70%, whereas cyclosporin A (CYP3A4 inhibitor, 100 μM) 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 μM). The American Society for Pharmacology and Experimental Therapeutics