title: Metabolism of 18-methoxycoronaridine, an ibogaine analog, to 18-hydroxycoronaridine by genetically variable CYP2C19.
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.
authors.affiliation: Center for Addiction and Mental Health, University of Toronto, Toronto, Canada.
authors.forename: Wenjiang
authors.initials: W
authors.lastname: Zhang
authors.forename: Yamini
authors.initials: Y
authors.lastname: Ramamoorthy
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.forename: Stanley D
authors.initials: SD
authors.lastname: Glick
authors.forename: Isabelle M
authors.initials: IM
authors.lastname: Maisonneuve
authors.forename: Martin E
authors.initials: ME
authors.lastname: Kuehne
authors.forename: Edward M
authors.initials: EM
authors.lastname: Sellers
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D014644:Genetic Variation; D006801:Humans; D007050:Ibogaine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013379:Substrate Specificity
chemical_list: C466182:18-hydroxycoronaridine; D000906:Antibodies; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D007050:Ibogaine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C113764:Cyp2c13 protein, rat; D065731:Cytochrome P-450 CYP2C19; D010089:Oxidoreductases, N-Demethylating; C103345:18-methoxycoronaridine