RT Journal Article
SR Electronic
T1 In Vitro Metabolism and Pharmacokinetic Studies on Methylone
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1247
OP 1255
DO 10.1124/dmd.112.050880
VO 41
IS 6
A1 Anders Just Pedersen
A1 Trine Hedebrink Petersen
A1 Kristian Linnet
YR 2013
UL http://dmd.aspetjournals.org/content/41/6/1247.abstract
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.