@article {Zhang663, author = {Wenjiang Zhang and Yamini Ramamoorthy and Rachel F. Tyndale and Stanley D. Glick and Isabelle M. Maisonneuve and Martin E. Kuehne and Edward M. Sellers}, title = {Metabolism of 18-Methoxycoronaridine, an Ibogaine Analog, to 18-Hydroxycoronaridine by Genetically Variable CYP2C19}, volume = {30}, number = {6}, pages = {663--669}, year = {2002}, doi = {10.1124/dmd.30.6.663}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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 (Km from 2.81 to 7.9 μM; Vmax from 0.045 to 0.29 nmol/mg/min). In cDNA-expressing microsomes, only CYP2C19 displayed significant 18-MC O-demethylase activity (Km 1.34 μM;Vmax 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 KI, 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 withS-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. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/30/6/663}, eprint = {https://dmd.aspetjournals.org/content/30/6/663.full.pdf}, journal = {Drug Metabolism and Disposition} }