Comparative in Vitro Studies of the Metabolism of Six 4-Substituted Methamphetamines and Their Inhibition of Cytochrome P450 2D6 by GC-MS with Trifluoroacetyl DerivatizationReport as inadecuate




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 - Download this document for free, or read online. Document in PDF available to download.

Use of new amphetamine-type stimulants ATS as designerdrugs is a serious problem worldwide. ATS are used in tablet, capsule, andpowder forms, and can be mixed with other drugs. There is little informationavailable on how these new drugs are metabolized or their ability to inhibitthe metabolism of co-administered drugs. This study aimed to investigatethe metabolism of six 4-substituted analogs of methamphetamine MA, and theirpotential 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 andGC-MS. The experiments showed that cytochrome P450 2D6 CYP2D6 was involved in the major metabolic pathway of MA, whereit 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-demethylationof 4-methoxymethamphetamine 4-MMA. The half maximal inhibitory concentration IC50values for CYP2D6 using MA as substrate were different for each of the4-substituted MAs. The strongest inhibitors of amphetamine production from MAwere, in order, 4-IMA, 4-BMA, 4-CMA, 4-MMA, 4-FMA, and 4-NMA. The same orderwas observed for the IC50 values for inhibition of p-hydroxymethamphetamineproduction from MA, except for the IC50 of 4-MMA. The IC50 values of 4-IMA were lower than the IC50 values of fluoxetine andhigher than that of quinidine. The results of this study imply that the risk of illicit drug interactionsfluctuates so widely that unintentionalfatal drug poisonings couldoccur.

KEYWORDS

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

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M. Taniguchi, Y. Yamamoto and K. Nishi -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,- American Journal of Analytical Chemistry, Vol. 4 No. 4, 2013, pp. 166-175. doi: 10.4236-ajac.2013.44022.





Author: Masashi Taniguchi, Yoshio Yamamoto, Katsuji Nishi

Source: http://www.scirp.org/



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