![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Molecular and Medical Pharmacology, University of
California, Los Angeles (L.Y.L., E.W.S., D.A.S., L.H., A.K.C.); and
University of Sheffield, Department of Medicine and Pharmacology, Royal
Hallamshire Hospital (S.W.E., M.S.L., G.T.T.)
Methamphetamine (MeAmp) abuse has recently experienced a resurgence
and approaches to the treatment of its addiction similar to those used
with cocaine have been considered. As the treatment regimes are likely
to use drugs whose metabolism is related to that of MeAmp, studies were
initiated to establish the enzymology of the fate of MeAmp.
This report describes investigations of the role of CYP2D6, the human
isoform of the enzyme that catalyzes debrisoquine hydroxylation, in the
4-hydroxylation and N-demethylation of MeAmp. The results of studies with human liver microsomes including those from a genetically poor metabolizer with respect to CYP2D6, showing
correlation between MeAmp and metoprolol hydroxylation and MDMA
demethylenation, were consistent with a major involvement of CYP2D6 in
the aromatic 4-hydroxylation of MeAmp. This was confirmed by studies
with recombinant CYP2D6 expressed in yeast, which was also shown to
effect the N-demethylation of MeAmp. The rate of the
4-hydroxylation reaction was substantially slower than the
demethylenation of MDMA. In contrast to MeAmp, MDMA was not
N-demethylated by CYP2D6. Since CYP2D6 participates in the
major steps of MeAmp metabolism, pharmacokinetic interactions are
likely with other drug substrates proposed for the treatment of MeAmp
addiction. Furthermore, the genetic polymorphism associated with the
enzyme could manifest itself in abnormal responses to MeAmp.
This article has been cited by other articles:
|
|
 |
|
  M. R. Meyer, F. T. Peters, and H. H. Maurer The Role of Human Hepatic Cytochrome P450 Isozymes in the Metabolism of Racemic 3,4-Methylenedioxy-Methamphetamine and Its Enantiomers Drug Metab. Dispos., November 1, 2008; 36(11): 2345 - 2354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Bonn, C. M. Masimirembwa, Y. Aristei, and I. Zamora The Molecular Basis of CYP2D6-Mediated N-Dealkylation: Balance between Metabolic Clearance Routes and Enzyme Inhibition Drug Metab. Dispos., November 1, 2008; 36(11): 2199 - 2210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Van, A. Heydari, J. Yang, J. Hargreaves, K. Rowland-Yeo, M. S. Lennard, G. T. Tucker, and A. Rostami-Hodjegan The impact of experimental design on assessing mechanism-based inactivation of CYP2D6 by MDMA (Ecstasy) J Psychopharmacol, November 1, 2006; 20(6): 834 - 841. [Abstract] [PDF]
|
|
|
|
 |
|
 W. Jeng, A. Ramkissoon, T. Parman, and P. G. Wells Prostaglandin H synthase-catalyzed bioactivation of amphetamines to free radical intermediates that cause CNS regional DNA oxidation and nerve terminal degeneration FASEB J, April 1, 2006; 20(6): 638 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. H. Wynn, K. L. Cozza, M. J. Zapor, G. W. Wortmann, and S. C. Armstrong Antiretrovirals, Part III: Antiretrovirals and Drugs of Abuse Psychosomatics, February 1, 2005; 46(1): 79 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Parrott Chronic tolerance to recreational MDMA (3,4-methylenedioxymethamphetamine) or Ecstasy J Psychopharmacol, January 1, 2005; 19(1): 71 - 83. [Abstract] [PDF]
|
|
|
|
|
|
A. Heydari, K. R. Yeo, M. S. Lennard, S. W. Ellis, G. T. Tucker, and A. Rostami-Hodjegan MECHANISM-BASED INACTIVATION OF CYP2D6 BY METHYLENEDIOXYMETHAMPHETAMINE Drug Metab. Dispos., November 1, 2004; 32(11): 1213 - 1217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Kalgutkar, S. Zhou, O. A. Fahmi, and T. J. Taylor Influence of Lipophilicity on the Interactions of N-Alkyl-4-phenyl-1,2,3,6-tetrahydropyridines and Their Positively Charged N-Alkyl-4-phenylpyridinium Metabolites with Cytochrome P450 2D6 Drug Metab. Dispos., May 1, 2003; 31(5): 596 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. I. Paine, L. A. McLaughlin, J. U. Flanagan, C. A. Kemp, M. J. Sutcliffe, G. C. K. Roberts, and C. R. Wolf Residues Glutamate 216 and Aspartate 301 Are Key Determinants of Substrate Specificity and Product Regioselectivity in Cytochrome P450 2D6 J. Biol. Chem., January 31, 2003; 278(6): 4021 - 4027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Y. L. Law, M. H. Slawson, and D. E. Moody Selective Involvement of Cytochrome P450 2D Subfamily in In Vivo 4-Hydroxylation of Amphetamine in Rat Drug Metab. Dispos., March 1, 2000; 28(3): 348 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Deng, B. Ladenheim, L.-I Tsao, and J. L. Cadet Null Mutation of c-fos Causes Exacerbation of Methamphetamine-Induced Neurotoxicity J. Neurosci., November 15, 1999; 19(22): 10107 - 10115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Fallon, A. T. Kicman, J. A. Henry, P. J. Milligan, D. A. Cowan, and A. J. Hutt Stereospecific Analysis and Enantiomeric Disposition of 3,4-Methylenedioxymethamphetamine (Ecstasy) in Humans Clin. Chem., July 1, 1999; 45(7): 1058 - 1069. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
