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Research ArticleArticle

Cytochrome P4502D6 Catalyzes the O-Demethylation of the Psychoactive Alkaloid Ibogaine to 12-Hydroxyibogamine

R. Scott Obach, John Pablo and Deborah C. Mash
Drug Metabolism and Disposition August 1998, 26 (8) 764-768;
R. Scott Obach
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John Pablo
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Deborah C. Mash
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Abstract

Ibogaine is a psychoactive alkaloid that possesses potential as an agent to treat opiate and cocaine addiction. The primary metabolite arises via O-demethylation at the 12-position to yield 12-hydroxyibogamine. In this report, evidence is presented that theO-demethylation of ibogaine observed in human hepatic microsomes is catalyzed primarily by the polymorphically expressed cytochrome P-4502D6 (CYP2D6). An enzyme kinetic examination of ibogaineO-demethylase activity in pooled human liver microsomes suggested that two (or more) enzymes are involved in this reaction: one with a low KMapp (1.1 μM) and the other with a high KMapp (>200 μM). The lowKMapp activity comprised >95% of total intrinsic clearance. Human liver microsomes from three individual donors demonstrated similar enzyme kinetic parameters (meanKMapp = 0.55 ± 0.09 μM and 310 ± 10 μM for low and high KMactivities, respectively). However, a fourth human microsome sample that appeared to be a phenotypic CYP2D6 poor metabolizer possessed only the high KMapp activity. In hepatic microsomes from a panel of human donors, the lowKMapp ibogaine O-demethylase activity correlated with CYP2D6-catalyzed bufuralol 1′-hydroxylase activity but not with other P450 isoform-specific activities. Quinidine, a CYP2D6-specific inhibitor, inhibited ibogaineO-demethylase (IC50 = 0.2 μM), whereas other P450 isoform-specific inhibitors did not inhibit this activity. Also, of a battery of recombinant heterologously expressed human P450 isoforms, only rCYP2D6 possessed significant ibogaineO-demethylase activity. Thus, it is concluded that ibogaineO-demethylase is catalyzed by CYP2D6 and that this isoform is the predominant enzyme of ibogaine O-demethylation in humans. The potential pharmacological implications of these findings are discussed.

Footnotes

  • Send reprint requests to: Dr. R. Scott Obach, Department of Drug Metabolism, Pfizer Central Research, Groton, CT 06340.

  • Abbreviation used is::
    P450
    cytochrome P450
    • Received January 19, 1998.
    • Accepted April 13, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 8
1 Aug 1998
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Research ArticleArticle

Cytochrome P4502D6 Catalyzes the O-Demethylation of the Psychoactive Alkaloid Ibogaine to 12-Hydroxyibogamine

R. Scott Obach, John Pablo and Deborah C. Mash
Drug Metabolism and Disposition August 1, 1998, 26 (8) 764-768;

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Research ArticleArticle

Cytochrome P4502D6 Catalyzes the O-Demethylation of the Psychoactive Alkaloid Ibogaine to 12-Hydroxyibogamine

R. Scott Obach, John Pablo and Deborah C. Mash
Drug Metabolism and Disposition August 1, 1998, 26 (8) 764-768;
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