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

R. Scott Obach, John Pablo, Deborah C Mash

Research output: Contribution to journalArticle

50 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)764-768
Number of pages5
JournalDrug Metabolism and Disposition
Volume26
Issue number8
StatePublished - Aug 1 1998
Externally publishedYes

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Ibogaine
Cytochromes
O Demethylating Oxidoreductases
Alkaloids
Protein Isoforms
Microsomes
Enzyme kinetics
Liver Microsomes
Enzymes
Liver
Opiate Alkaloids
Opioid-Related Disorders
Cocaine-Related Disorders
Quinidine
noribogaine
Metabolites
Cocaine
Kinetic parameters
Inhibitory Concentration 50
Pharmacology

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Cytochrome P4502D6 catalyzes the O-demethylation of the psychoactive alkaloid ibogaine to 12-hydroxyibogamine. / Obach, R. Scott; Pablo, John; Mash, Deborah C.

In: Drug Metabolism and Disposition, Vol. 26, No. 8, 01.08.1998, p. 764-768.

Research output: Contribution to journalArticle

Obach, R. Scott ; Pablo, John ; Mash, Deborah C. / Cytochrome P4502D6 catalyzes the O-demethylation of the psychoactive alkaloid ibogaine to 12-hydroxyibogamine. In: Drug Metabolism and Disposition. 1998 ; Vol. 26, No. 8. pp. 764-768.
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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 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.",
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