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Vol. 29, Issue 6, 887-890, June 2001
Department of Hospital Pharmacy, Tokyo Postal Services Agency
Hospital, Chiyoda-ku, Tokyo, Japan (Y.Yanagihara, S.K., M.O., K.U.) and
Department of Pharmacy, The University of Tokyo Hospital, Faculty of
Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan (T.A.,
Y.Yamamura, T.I.)
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 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 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 µM, 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 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).
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