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Stereoselectivity in the cytochrome P450-dependent N-demethylation and flavin monooxygenase-dependent N-oxidation of N,N-dimethylamphetamine

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Abstract

N,N-Dimethylamphetamine (DMA), a methamphetamine (MA) analog, is known as a weak central nervous system stimulant. As DMA possesses a chiral center, we investigated the enantioselective formation of N,N-dimethylamphetamine N-oxide (DMANO) and MA from DMA using human liver microsomes, recombinant cytochrome P450 (CYP) 2D6, and flavin monooxygenases (FMO) 1 and 3. d-DMA was preferentially metabolized to MA, whereas l-DMA was more rapidly transformed to DMANO in human liver microsomes. CYP2D6 showed a preference for catalyzing N-demethylation of d-DMA, and the intrinsic clearance (Clint) ratio of d-isomer to l-isomer was 1.41. FMO1 catalyzed the formation of slightly less d-DMANO than l-DMANO, and the Clint ratio of the d- to l-isomer was 0.78. The reverse was observed for the formation of DMANO by FMO3. However, given the minor contribution of FMO3 compared with FMO1, it would not affect the overall enantioselective formation of DMANO in human liver microsomes. Enantioselectivities in the formation of MA and DMANO in human liver microsomes were consistent with those of CYP2D6 and FMO1, respectively.

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Acknowledgments

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MEST) (No. R13-2007-023-00000-0).

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Authors and Affiliations

  1. College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 702-701, South Korea

    Sangkyu Lee

  2. College of Pharmacy, Hanyang University, Gyeonggi-do, Ansan-si, 426-791, South Korea

    Hye Hyun Yoo

  3. Drug Signature Analysis Center, Supreme Prosecutors’ Office, Seoul, South Korea

    Moon Kyo In

  4. Doping Control Center, Korea Institute of Science and Technology, PO Box 131, Chungryang, Seoul, South Korea

    Changbae Jin

  5. Department of Pharmacology and PharmacoGenomics Research Center, Inje University, College of Medicine, #633-165 Gaegum-Dong, Jin-Gu, Pusan, 614-735, South Korea

    Dong Hyun Kim

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  1. Sangkyu Lee
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  2. Hye Hyun Yoo
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  3. Moon Kyo In
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  4. Changbae Jin
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Correspondence to Dong Hyun Kim.

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Lee, S., Yoo, H.H., In, M.K. et al. Stereoselectivity in the cytochrome P450-dependent N-demethylation and flavin monooxygenase-dependent N-oxidation of N,N-dimethylamphetamine. Arch. Pharm. Res. 36, 1385–1391 (2013). https://doi.org/10.1007/s12272-013-0137-z

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