Metabolism of 18-methoxycoronaridine, an ibogaine analog, to 18-hydroxycoronaridine by genetically variable CYP2C19.
Wenjiang Zhang, Yamini Ramamoorthy, Rachel F. Tyndale, Stanley D Glick, Isabelle M Maisonneuve, Martin E. Kuehne, Edward M. Sellers
Drug Metabolism and Disposition June 1, 2002 DOI: 10.1124/dmd.30.6.663 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | Human liver microsomes and cDNA-expressing microsomes |
| Topics | Ibogaine |
| Keywords | Drug metabolism Addiction treatment Cyp2c19 enzyme Pharmacokinetics Drug response variability |
| Citations | 17 |
| Key points | 18-MC is primarily metabolized to 18-HC by the polymorphic CYP2C19 enzyme in human liver microsomes. |
Abstract
18-Methoxycoronaridine, a newly developed ibogaine analog, has been reported to decrease the self-administration of morphine, cocaine, ethanol, and nicotine. It has also been reported to attenuate naltrexone-precipitated signs of morphine withdrawal. In this study, three metabolites of 18-methoxycoronaridine (18-MC) were separated and identified by high-performance liquid chromatography-electrospray ionization-mass spectrometry-mass spectrometry (HPLC-ESI-MS-MS); the major metabolite was 18-hydroxycoronaridine (18-HC). The other two metabolites were elucidated as hydroxylated metabolites on the basis of their MS-MS spectra. Catalytic studies of 18-MC O-demethylase activity in human liver microsomes indicate that one high affinity enzyme is involved in this reaction (K(m) from 2.81 to 7.9 microM; V(max) from 0.045 to 0.29 nmol/mg/min). In cDNA-expressing microsomes, only CYP2C19 displayed significant 18-MC O-demethylase activity (K(m) 1.34 microM; V(max) 0.21 nmol/mg/min). S-Mephenytoin, a selective CYP2C19 inhibitor, inhibited 18-MC O-demethylation by 65% at a concentration of 2 times its K(I), and antibodies against rat 2C (human CYP2C8, 2C9, 2C19) inhibited 18-HC formation by 70%. Studies with other cytochrome P450 (P450)-selective chemical inhibitors and antibodies failed to demonstrate an appreciable role for other P450s in this reaction. In addition, in microsomes from five different human livers, 18-MC O-demethylation correlated with S-mephenytoin 4'hydroxylase activity but not with other P450 probe reactions. These data indicate that 18-HC formation is the predominant pathway of 18-MC metabolism in vitro in human liver microsomes and that this metabolic pathway is primarily catalyzed by the polymorphic CYP2C19. The apparent selectivity of this pathway for CYP2C19 suggests 18-MC as a potentially useful probe of CYP2C19 activity in vitro and in vivo.
Comparable studies
Other preclinical and animal studies on ibogaine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Noncompetitive Functional Inhibition at Diverse, Human Nicotinic Acetylcholine Receptor Subtypes by Bupropion, Phencyclidine, and Ibogaine TE671/RD cells (human muscle-type nAChR) and SH-SY5Y neuroblastoma cells (human... | 1999 | In vitro study | |
| Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline. Ibogaine- or harmaline-treated rats | 1993 | Experimental animal study | |
| Effects and aftereffects of ibogaine on morphine self-administration in rats. Rats | 1991 | Preclinical experimental study | |
| Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum. Rats | 1994 | Experimental study | |
| Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption Rats | 2005 | Experimental study |
Citations in the library
Cited by 7
- The Anti-Addiction Drug Ibogaine and the Heart: A Delicate Relation Molecules January 29, 2015
- Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment. Pharmacology, Biochemistry, and Behavior June 1, 2003
- DARK Classics in Chemical Neuroscience: Ibogaine ACS Chemical Neuroscience September 14, 2018
- Three Decades of Research on the Development of Ibogaine Treatment of Substance Use Disorders: A Scientometric Analysis. Journal of Psychoactive Drugs 2024
- Selectivity of coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula. The international journal of biochemistry & cell biology October 16, 2017
and 2 more in the library
Cites 10
- Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline. Neuroscience July 1, 1993
- Treatment of acute opioid withdrawal with ibogaine. American Journal on Addictions 1999
- Effects and aftereffects of ibogaine on morphine self-administration in rats. European Journal of Pharmacology April 3, 1991
- Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum. Brain Research September 19, 1994
- Inhibitory effects of ibogaine on cocaine self-administration in rats. European Journal of Pharmacology September 14, 1993
and 5 more in the library