TY - JOUR

T1 - In vitro metabolism and pharmacokinetic studies on methylone

AU - Pedersen, Anders Just

AU - Petersen, Trine Hedebrink

AU - Linnet, Kristian

PY - 2013/6

Y1 - 2013/6

N2 - 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: V(max,1) = 0.046 ± 0.005 (S.E.) nmol/min/mg protein, K(m,1) = 19.0 ± 4.2 μM, V(max,2) = 0.22 ± 0.04 nmol/min/mg protein, and K(m,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 K(I) = 15.1 ± 3.4 (S.E.) μM and k(inact) = 0.075 ± 0.005 minute(-1).

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: V(max,1) = 0.046 ± 0.005 (S.E.) nmol/min/mg protein, K(m,1) = 19.0 ± 4.2 μM, V(max,2) = 0.22 ± 0.04 nmol/min/mg protein, and K(m,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 K(I) = 15.1 ± 3.4 (S.E.) μM and k(inact) = 0.075 ± 0.005 minute(-1).

U2 - 10.1124/dmd.112.050880

DO - 10.1124/dmd.112.050880

M3 - Journal article

C2 - 23545806

VL - 41

SP - 1247

EP - 1255

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

IS - 6

ER -