Vol. 26, Issue 8, 764-768, August 1998

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

R. Scott Obach, John Pablo, and Deborah C. Mash

Department of Drug Metabolism, Central Research Division (R. S. O.), Pfizer, Inc., and Departments of Neurology and Pharmacology (J. P., D. C. M.), University of Miami School of Medicine

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 the O-demethylation of ibogaine observed in human hepatic microsomes is catalyzed primarily by the polymorphically expressed cytochrome P-4502D6 (CYP2D6). An enzyme kinetic examination of ibogaine O-demethylase activity in pooled human liver microsomes suggested that two (or more) enzymes are involved in this reaction: one with a low K_Mapp (1.1 µM) and the other with a high K_Mapp (>200 µM). The low K_Mapp activity comprised >95% of total intrinsic clearance. Human liver microsomes from three individual donors demonstrated similar enzyme kinetic parameters (mean K_Mapp = 0.55 ± 0.09 µM and 310 ± 10 µM for low and high K_M activities, respectively). However, a fourth human microsome sample that appeared to be a phenotypic CYP2D6 poor metabolizer possessed only the high K_Mapp activity. In hepatic microsomes from a panel of human donors, the low K_Mapp 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 ibogaine O-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 ibogaine O-demethylase activity. Thus, it is concluded that ibogaine O-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.