PT - JOURNAL ARTICLE AU - Anders Just Pedersen AU - Trine Hedebrink Petersen AU - Kristian Linnet TI - In Vitro Metabolism and Pharmacokinetic Studies on Methylone AID - 10.1124/dmd.112.050880 DP - 2013 Jun 01 TA - Drug Metabolism and Disposition PG - 1247--1255 VI - 41 IP - 6 4099 - http://dmd.aspetjournals.org/content/41/6/1247.short 4100 - http://dmd.aspetjournals.org/content/41/6/1247.full SO - Drug Metab Dispos2013 Jun 01; 41 AB - Abuse of the stimulant designer drug methylone (methylenedioxymethcathinone) has been documented in most parts of the world. As with many of the new designer drugs that continuously appear in the illicit drug market, little is known about the pharmacokinetics of methylone. Using in vitro studies, CYP2D6 was determined to be the primary enzyme that metabolizes methylone, with minor contributions from CYP1A2, CYP2B6, and CYP2C19. The major metabolite was identified as dihydroxymethcathinone, and the minor metabolites were N-hydroxy-methylone, nor-methylone, and dihydro-methylone. Measuring the formation of the major metabolite, biphasic Michaelis–Menten kinetic parameters were determined: Vmax,1 = 0.046 ± 0.005 (S.E.) nmol/min/mg protein, Km,1 = 19.0 ± 4.2 μM, Vmax,2 = 0.22 ± 0.04 nmol/min/mg protein, and Km,2 = 1953 ± 761 μM; the low-capacity and high-affinity contribution was assigned to the activity of CYP2D6. Additionally, a time-dependent loss of CYP2D6 activity was observed when the enzyme was preincubated with methylone, reaching a maximum rate of inactivation at high methylone concentrations, indicating that methylone is a mechanism-based inhibitor of CYP2D6. The inactivation parameters were determined to be KI = 15.1 ± 3.4 (S.E.) μM and kinact = 0.075 ± 0.005 minute−1.