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Research ArticleArticle

Involvement of CYP2B6 in N-Demethylation of Ketamine in Human Liver Microsomes

Yoshitsugu Yanagihara, Satoru Kariya, Michiteru Ohtani, Katsuyoshi Uchino, Takao Aoyama, Yoshikazu Yamamura and Tatsuji Iga
Drug Metabolism and Disposition June 2001, 29 (6) 887-890;
Yoshitsugu Yanagihara
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Satoru Kariya
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Michiteru Ohtani
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Katsuyoshi Uchino
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Takao Aoyama
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Yoshikazu Yamamura
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Tatsuji Iga
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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 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).

Footnotes

  • Send reprint requests to: Yoshitsugu Yanagihara, Department of Hospital Pharmacy, Tokyo Postal Services Agency Hospital, 2-14-23 Fujimi, Chiyoda-ku, Tokyo 102-8798 Japan. E-mail:yyanagihara{at}tpth.go.jp

  • Abbreviations used are::
    CYP
    cytochrome P450
    CLint
    intrinsic clearance
    G-6-P
    glucose 6-phosphate
    NADP
    nicotinamide-adenine dinucleotide phosphate
    HPLC
    high performance liquid chromatography
    • Received October 3, 2000.
    • Accepted February 1, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (6)
Drug Metabolism and Disposition
Vol. 29, Issue 6
1 Jun 2001
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Research ArticleArticle

Involvement of CYP2B6 in N-Demethylation of Ketamine in Human Liver Microsomes

Yoshitsugu Yanagihara, Satoru Kariya, Michiteru Ohtani, Katsuyoshi Uchino, Takao Aoyama, Yoshikazu Yamamura and Tatsuji Iga
Drug Metabolism and Disposition June 1, 2001, 29 (6) 887-890;

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Research ArticleArticle

Involvement of CYP2B6 in N-Demethylation of Ketamine in Human Liver Microsomes

Yoshitsugu Yanagihara, Satoru Kariya, Michiteru Ohtani, Katsuyoshi Uchino, Takao Aoyama, Yoshikazu Yamamura and Tatsuji Iga
Drug Metabolism and Disposition June 1, 2001, 29 (6) 887-890;
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