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Rapid CommunicationShort Communication

N-Oxygenation of Clozapine by Flavin-Containing Monooxygenase

Meera Tugnait, Edward M. Hawes, Gordon McKay, Allan E. Rettie, Robert L. Haining and Kamal K. Midha
Drug Metabolism and Disposition April 1997, 25 (4) 524-527;
Meera Tugnait
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Edward M. Hawes
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Gordon McKay
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Allan E. Rettie
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Robert L. Haining
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Kamal K. Midha
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Abstract

The involvement of FMO in the N-oxygenation of CLZ was investigated by use of purified FMOs and human liver microsomes that contained the mean amount of immunoreactive FMO3 relative to other human liver microsomal preparations in a liver bank. In the microsomal preparation the involvement of FMO was indicated through enzyme inhibition by methimazole, heat inactivation, and protection against heat inactivation by NADPH. Also the Michaelis-Menten kinetic constant;KM determined for CLZ N-oxidation catalyzed by purified human FMO3 (324 μM) was very similar to the mean value obtained in these laboratories for the microsomal preparations of seven human livers.

Footnotes

  • Send reprint requests to: Dr. Edward M. Hawes, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, SK, S7N 5C9, Canada.

  • Received September 5, 1996; accepted January 24, 1997.

  • This study was supported by the Medical Research Council of Canada, Program Grant PG-11472 (to K.K.M., E.M.H., G.M.). These data were presented in abstract form at the 7th North American ISSX Meeting, held in San Diego, CA, from October 19–24, 1996 [ISSX Proc.10, 221 (1996)].

  • ↵2 M. Tugnait et al., unpublished observations.

  • ↵3 R. L. Haining, A. P. Hunter, A. J. M. Sadeque, R. M. Philpot, and A. E. Rettie: Baculovirus-mediated expression and purification of human FMO3: catalytic, immunochemical and structural characterization. Drug. Metab. Disp. Submitted for publication.

  • Abbreviations used are::
    CLZ
    clozapine
    CYP
    cytochrome P450
    FMO
    flavin-containing monooxygenase
    TCA
    trichloroacetic acid
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 4
1 Apr 1997
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Rapid CommunicationShort Communication

N-Oxygenation of Clozapine by Flavin-Containing Monooxygenase

Meera Tugnait, Edward M. Hawes, Gordon McKay, Allan E. Rettie, Robert L. Haining and Kamal K. Midha
Drug Metabolism and Disposition April 1, 1997, 25 (4) 524-527;

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Rapid CommunicationShort Communication

N-Oxygenation of Clozapine by Flavin-Containing Monooxygenase

Meera Tugnait, Edward M. Hawes, Gordon McKay, Allan E. Rettie, Robert L. Haining and Kamal K. Midha
Drug Metabolism and Disposition April 1, 1997, 25 (4) 524-527;
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