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Cytochrome P4502D6 catalyzes the O-demethylation of the psychoactive alkaloid ibogaine to 12-hydroxyibogamine.
Drug Metab Dispos. 1998 Aug; 26(8):764-8.DM

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+Show Affiliations

Department of Drug Metabolism, Central Research Division, Pfizer, Inc., Groton, CT 06340, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9698290

Citation

Obach, R S., et al. "Cytochrome P4502D6 Catalyzes the O-demethylation of the Psychoactive Alkaloid Ibogaine to 12-hydroxyibogamine." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 26, no. 8, 1998, pp. 764-8.
Obach RS, Pablo J, Mash DC. Cytochrome P4502D6 catalyzes the O-demethylation of the psychoactive alkaloid ibogaine to 12-hydroxyibogamine. Drug Metab Dispos. 1998;26(8):764-8.
Obach, R. S., Pablo, J., & Mash, D. C. (1998). Cytochrome P4502D6 catalyzes the O-demethylation of the psychoactive alkaloid ibogaine to 12-hydroxyibogamine. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 26(8), 764-8.
Obach RS, Pablo J, Mash DC. Cytochrome P4502D6 Catalyzes the O-demethylation of the Psychoactive Alkaloid Ibogaine to 12-hydroxyibogamine. Drug Metab Dispos. 1998;26(8):764-8. PubMed PMID: 9698290.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cytochrome P4502D6 catalyzes the O-demethylation of the psychoactive alkaloid ibogaine to 12-hydroxyibogamine. AU - Obach,R S, AU - Pablo,J, AU - Mash,D C, PY - 1998/8/11/pubmed PY - 1998/8/11/medline PY - 1998/8/11/entrez SP - 764 EP - 8 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 26 IS - 8 N2 - 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. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/9698290/Cytochrome_P4502D6_catalyzes_the_O_demethylation_of_the_psychoactive_alkaloid_ibogaine_to_12_hydroxyibogamine_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9698290 DB - PRIME DP - Unbound Medicine ER -