Cytochrome P4502D6 catalyzes the O-demethylation of the psychoactive alkaloid ibogaine to 12-hydroxyibogamine.

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 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 KMapp (1.1 microM) and the other with a high KMapp (>200 microM). The low KMapp activity comprised >95% of total intrinsic clearance. Human liver microsomes from three individual donors demonstrated similar enzyme kinetic parameters (mean KMapp = 0.55 +/- 0.09 microM and 310 +/- 10 microM for low and high KM activities, 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 low KMapp 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 microM), 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.

• Authors: R S Obach, J Pablo, D C Mash
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 26 Issue 8 Pg. 764-8 (Aug 1998) ISSN: 0090-9556 [Print] United States
• PMID: 9698290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytochrome P-450 CYP2D6 Inhibitors
• Enzyme Inhibitors
• Hallucinogens
• Isoenzymes
• Ibogaine
• noribogaine
• Cytochrome P-450 CYP2D6

Topics

• Cytochrome P-450 CYP2D6 (metabolism)
• Cytochrome P-450 CYP2D6 Inhibitors
• Enzyme Inhibitors (pharmacology)
• Hallucinogens (metabolism)
• Humans
• Ibogaine (analogs & derivatives, metabolism)
• Isoenzymes (antagonists & inhibitors, metabolism)
• Kinetics
• Methylation
• Microsomes, Liver (enzymology)