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The Role of Human UDP-glucuronyltransferases on the Formation of the Methylenedioxymethamphetamine (

The Role of Human UDP-glucuronyltransferases on the Formation of the Methylenedioxymethamphetamine (

  1. Jatelka
    Drug Metabolism and Disposition 2009 Aug 10. [Epub ahead of print]

    Schwaninger AE, Meyer MR, Zapp J, Maurer HH.

    Different pharmacokinetic properties have been observed for the two enantiomers of the entactogen 3,4-methylendioxy-methamphetamine (MDMA), most probably due to enantioselective metabolism. The aim of the present work was to study the involvement of human UDP-glucuronyltransferase (UGT) isoforms in the glucuronidation of the enantiomers of its major metabolite 4-hydroxy 3-methoxymethamphetmine (HMMA). First, the reference standards of R- and S-HMMA O-glucuronide were synthesized semi-preparatively using the enzymes of rat liver microsomes, followed by isolation with semi-preparative HPLC and identification using mass spectrometry and NMR. Racemic HMMA was then incubated using heterologously expressed human UGTs and pooled human liver microsomes, and the glucuronides were quantified by liquid chromatography-linear ion trap-mass spectrometry. UGT1A1, UGT1A3, UGT1A8, UGT1A9, UGT2B4, UGT2B7, UGT2B15 and UGT2B17 were involved in the glucuronidation of HMMA. UGT2B15, UGT2B17 and HLM revealed classical Michaelis-Menten kinetics, whereas UGT1A9 and UGT2B7 showed sigmoidal curves and the respective Eadie Hofstee plots indicated autoactivation kinetics. UGT2B15 showed the highest affinity and activity. UGT2B15, UGT2B17 and HLM were not considerably enantioselective, but showed slight preferences for S-HMMA. Marked enantioselectivity could only be observed for UGT1A9 with respect to the S-enantiomer, and for UGT2B7 with respect to the R-enantiomer. In conclusion the O-glucuronidation of HMMA in vivo should not be expected to be enantioselective and the different pharmacokinetic properties may not be caused directly by glucuronidation.