Stereoselective differences in the cytochrome P450-dependent dealkylation and demethylenation of -methyl-benzodioxolyl-butanamine (MBDB, Eden) enantiomers

Markus R. Meyer , Frank T. Peters , Hans H. Maurer

In the present study, cytochrome P450 isozymes (P450) involved in the stereoselective metabolism of the designer drug -methyl-benzodioxolyl-butanamine (MBDB, Eden) were identified for the first time. Demethylenation and -demethylation of racemic MBDB as well as its single enantiomers were investigated using cDNA expressed insect cell microsomes. After incubation of MBDB, the two resulting main metabolites 1,2-dihydroxy-4-[2-(methylamino)butyl]benzene (DHMBB) and benzodioxolyl-butanamine (BDB) were separated and quantified by achiral gas chromatography-mass spectrometry after chiral derivatization with -heptafluorobutyrylprolyl chloride. Dealkylation was mainly catalyzed by CYP2B6 and CYP2C19, demethylenation was additionally catalyzed by CYP1A2, CYP2D6, and CYP3A4. The most abundant isozymes after correlation using the relative activity factor approach are CYP2B6 for -dealkylation and CYP2D6 for demethylenation the second step being the most relevant. In addition, inhibition studies towards MBDB biotransformation using the CYP2D6 selective inhibitor quinidine confirmed the dominant role of this polymorphic isozyme in total MBDB metabolism. In general, at low substrate concentrations the enantiomer is metabolized at a higher rate foremost by CYP2C19. These findings are in line with results previously reported for the corresponding ring substituted amphetamines 3,4-methylenedioxy-methamphetamine and 3,4-methylenedioxy-ethylamphetamine. In conclusion, the main enzyme responsible for MBDB metabolism after correlation is CYP2D6, whereas CYP2C19 is the most enantioselective.

Mots clés: MBDB; Amphetamines; Enantiomers; CYP; Enzyme kinetic; Inhibition

Markus R. Meyer, Frank T. Peters, Hans H. Maurer. Stereoselective differences in the cytochrome P450-dependent dealkylation and demethylenation of -methyl-benzodioxolyl-butanamine (MBDB, Eden) enantiomers. Biochemical Pharmacology, 2009, 77 (11), pp.1725. ⟨10.1016/j.bcp.2009.03.001⟩. ⟨hal-00493501⟩