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Research ArticleArticle

A Significant Role of Human Cytochrome P450 2C8 in Amiodarone N-Deethylation: An Approach to Predict the Contribution with Relative Activity Factor

Katsuhiro Ohyama, Miki Nakajima, Sumika Nakamura, Noriaki Shimada, Hiroshi Yamazaki and Tsuyoshi Yokoi
Drug Metabolism and Disposition November 2000, 28 (11) 1303-1310;
Katsuhiro Ohyama
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Miki Nakajima
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Sumika Nakamura
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Noriaki Shimada
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Hiroshi Yamazaki
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Tsuyoshi Yokoi
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Abstract

Human cytochrome P450 (CYP) isoforms involved in amiodaroneN-deethylation were identified, and the relative contributions of these CYP isoforms were evaluated in different human liver microsomes. The mean KM andVmax values of amiodaroneN-deethylation in microsomes from six human livers were 31.6 ± 7.5 μM and 1.2 ± 0.7 pmol/min/pmol of CYP, respectively. Ketoconazole and anti-CYP3A antibodies strongly inhibited amiodarone N-deethylase activity in human liver microsomes at a substrate concentration of 50 μM. Of 15 recombinant human CYP enzymes (19 preparations), CYP1A1, CYP3A4, CYP1A2, CYP2D6, CYP2C8, and CYP2C19 catalyzed amiodarone N-deethylation. The amiodarone N-deethylase activity at a substrate concentration of 5 μM was significantly correlated with the paclitaxel 6α-hydroxylase activity (r = 0.84,P < .05) in the human liver microsomes, whereas the amiodarone N-deethylase activity at 100 μM was significantly correlated with the testosterone 6β-hydroxylase activity (r = 0.94, P < .005). According to the concept of relative activity factor, it was clarified that CYP2C8 as well as CYP3A4 were significantly involved in amiodarone N-deethylation in human livers at clinically significant concentrations and that the contributions of CYP1A2, CYP2C19, and CYP2D6 were relatively minor. However, there was a large interindividual variability in the contribution of each CYP isoform to amiodarone N-deethylase activity in human liver; the relevance of these enzymes would be dependent on the content of the respective isoforms and on the amiodarone concentration in the liver.

Footnotes

  • Send reprint requests to: Tsuyoshi Yokoi, Ph.D., Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa 920-0934, Japan. E-mail:tyokoi{at}kenroku.kanazawa-u.ac.jp

  • A part of this study was supported by a grant-in-aid from the Ministry of Education, Science, Sports, and Culture of Japan.

  • Abbreviations used are::
    CYP
    cytochrome P450
    b5
    cytochromeb5
    CL
    clearance
    OR
    NADPH-cytochrome P450 oxidoreductase
    RAF
    relative activity factor
    • Received March 16, 2000.
    • Accepted July 26, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (11)
Drug Metabolism and Disposition
Vol. 28, Issue 11
1 Nov 2000
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Research ArticleArticle

A Significant Role of Human Cytochrome P450 2C8 in Amiodarone N-Deethylation: An Approach to Predict the Contribution with Relative Activity Factor

Katsuhiro Ohyama, Miki Nakajima, Sumika Nakamura, Noriaki Shimada, Hiroshi Yamazaki and Tsuyoshi Yokoi
Drug Metabolism and Disposition November 1, 2000, 28 (11) 1303-1310;

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Research ArticleArticle

A Significant Role of Human Cytochrome P450 2C8 in Amiodarone N-Deethylation: An Approach to Predict the Contribution with Relative Activity Factor

Katsuhiro Ohyama, Miki Nakajima, Sumika Nakamura, Noriaki Shimada, Hiroshi Yamazaki and Tsuyoshi Yokoi
Drug Metabolism and Disposition November 1, 2000, 28 (11) 1303-1310;
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