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

Masashi Taniguchi, Yoshio Yamamoto, Katsuji Nishi

Department of Legal Medicine, Shiga University of Medical Science, Otsu, Shiga.
Forensic Science Laboratory, Shiga Police Headquarters, Otsu, Japan.
Laboratory of Environmental Chemistry, Iga Research Institute of Mie University, Mie, Japan.

DOI: 10.4236/ajac.2013.44022                

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.

Keywords

Methamphetamine; Designer Drug; GC-MS; TFA Derivatization; Interaction; Metabolism

Conflicts of Interest

The authors declare no conflicts of interest.

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