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
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|