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.
Highlights
Designer drugs are a serious problem worldwide, especially among young people, and in some cases they have resulted in fatal poisoning [1,2,3,4,5,6,7]
Similar findings were reported by Kuwayama et al and Lin et al, who found that cytochrome P450 2D6 (CYP2D6) was the main enzyme that metabolized 3,4-methylenedioxymethamphetamine (MDMA) [24,25]
This study investigated the in vitro metabolism of six 4substituted MAs and their potential inhibition of MA metabolism using human metabolic enzymes by gas chromatography-mass spectrometry (GC-MS) after Trifluoroacetic anhydride (TFA) derivatization
Summary
Designer drugs are a serious problem worldwide, especially among young people, and in some cases they have resulted in fatal poisoning [1,2,3,4,5,6,7]. New designer drugs are created by changing the molecular structure of an existing drug. 4-methoxymethamphetamine (4MMA) and 4-fluoromethamphetamine (4-FMA), which are 4-substituted psychoactive analogs of methamphetamine (MA), have emerged on the illicit drug market [1,2, 8,9,10,11]. Designer drugs such as illicit amphetamine-type stimulants are often co-administered with other drugs in tablet, capsule, or powder form [12,13,14,15,16,17]. The emergence of new designer drugs and co-administration of drugs have made it difficult to discriminate controlled substances in forensic samples, and have increased drug-related problems
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