Metabolism of 18-methoxycoronaridine, an ibogaine analog, to 18-hydroxycoronaridine by genetically variable CYP2C19

Drug Metab Dispos. 2002 Jun;30(6):663-9. doi: 10.1124/dmd.30.6.663.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Aryl Hydrocarbon Hydroxylases*
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / immunology
  • Cytochrome P-450 Enzyme System / metabolism*
  • DNA, Complementary / genetics
  • Enzyme Inhibitors / pharmacology
  • Genetic Variation
  • Humans
  • Ibogaine / analogs & derivatives*
  • Ibogaine / metabolism*
  • Ibogaine / pharmacokinetics
  • In Vitro Techniques
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Mixed Function Oxygenases / genetics
  • Mixed Function Oxygenases / metabolism*
  • Oxidoreductases, N-Demethylating / metabolism
  • Rats
  • Spectrometry, Mass, Electrospray Ionization
  • Substrate Specificity

Substances

  • 18-hydroxycoronaridine
  • Antibodies
  • DNA, Complementary
  • Enzyme Inhibitors
  • Ibogaine
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cyp2c13 protein, rat
  • Cytochrome P-450 CYP2C19
  • Oxidoreductases, N-Demethylating
  • 18-methoxycoronaridine