Stereoselective differences in the cytochrome P450-dependent dealkylation and demethylenation of N-methyl-benzodioxolyl-butanamine (MBDB, Eden) enantiomers.
In the present study, cytochrome P450 isozymes (P450) involved in the stereoselective metabolism of the designer drug N-methyl-benzodioxolyl-butanamine (MBDB, Eden) were identified for the first time. Demethylenation and N-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 S-heptafluorobutyrylprolyl chloride. Dealkylation was mainly catalyzed by CYP2B6 and CYP2C19, demethylenation was additionally catalyzed by CYP1A2, CYP2D6, and CYP3A4. The most abundant isozymes after in vitro-in vivo correlation using the relative activity factor approach are CYP2B6 for N-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 S-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 in vitro-in vivo correlation is CYP2D6, whereas CYP2C19 is the most enantioselective.
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, D-66421 Homburg (Saar), Germany.
Markus R
MR
Meyer
Frank T
FT
Peters
Hans H
HH
Maurer
D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003640:Dealkylation; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007700:Kinetics; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity
C051570:N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine; D015104:3,4-Methylenedioxyamphetamine; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating