TITLE:
Comparative in Vitro Studies of the Metabolism of Six 4-Substituted Methamphetamines and Their Inhibition of Cytochrome P450 2D6 by GC-MS with Trifluoroacetyl Derivatization
AUTHORS:
Masashi Taniguchi, Yoshio Yamamoto, Katsuji Nishi
KEYWORDS:
Methamphetamine; Designer Drug; GC-MS; TFA Derivatization; Interaction; Metabolism
JOURNAL NAME:
American Journal of Analytical Chemistry,
Vol.4 No.4,
April
29,
2013
ABSTRACT: Use of new amphetamine-type stimulants (ATS) as designer
drugs is a serious problem worldwide. ATS are used in tablet, capsule, and
powder forms, and can be mixed with other drugs. There is little information
available on how these new drugs are metabolized or their ability to inhibit
the metabolism of co-administered drugs. This study aimed to investigate
the metabolism of six 4-substituted analogs of methamphetamine (MA), and their
potential inhibition of MA metabolism. The metabolism of MA and the 4-substituted MAs was examined in vitro using human metabolic enzymes.
Metabolite analyses were performed using trifluoroacetyl derivatization and
GC-MS. The experiments showed that cytochrome P450 2D6 (CYP2D6) was involved in the major metabolic pathway of MA, where
it catalyzed N-demethylation of 4-fluoromethamphetamine (4-FMA),
4-chloromethamphetamine (4-CMA), 4-bromomethamphetamine (4-BMA), 4-iodomethamphetamine (4-IMA) and 4-nitromethamphetamine (4-NMA),
and O-demethylation
of 4-methoxymethamphetamine (4-MMA). The half maximal inhibitory concentration (IC50)
values for CYP2D6 using MA as substrate were different for each of the
4-substituted MAs. The strongest inhibitors of amphetamine production from MA
were, in order, 4-IMA, 4-BMA, 4-CMA, 4-MMA, 4-FMA, and 4-NMA. The same order
was observed for the IC50 values for inhibition of p-hydroxymethamphetamine
production from MA, except for the IC50 of 4-MMA. The IC50 values of 4-IMA were lower than the IC50 values of fluoxetine and
higher than that of quinidine. The results of this study imply that the risk of illicit drug interactions
fluctuates so widely that unintentional
fatal drug poisonings could
occur.