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Toxicol Lett. 2018 Mar 15;285:1-8. doi: 10.1016/j.toxlet.2017.12.017. Epub 2017 Dec 23.

Human cytochrome P450 kinetic studies on six N-2-methoxybenzyl (NBOMe)-derived new psychoactive substances using the substrate depletion approach.

Author information

1
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
2
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany. Electronic address: hans.maurer@uks.eu.

Abstract

A huge number of new chemical derivatives of known drugs of abuse, so-called new psychoactive substances (NPS), are sold and consumed without prior preclinical and clinical testing. For assessing the elimination behaviors, determination of the kinetic constants Km and Vmax of the cytochrome P450 (CYP) isoforms involved in the hepatic metabolism of NPS could help to predict their contributions to hepatic clearance, drug-drug interactions and polymorphisms. Therefore, the aims of the present study were to determine the Km and Vmax values for CYP isoforms using the substrate depletion approach for the six N-2-methoxybenzyl (NBOMe)-derived NPS 25B-NBOMe, 25C-NBOMe, 25I-NBOMe, 3,4-DMA-NBOMe, 4-EA-NBOMe, and 4-MMA-NBOMe. Furthermore, the contributions of each CYP isozyme to the hepatic net clearance were elucidated using the relative activity factor approach. Several CYPs including CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP3A4 were identified to be involved in the metabolism of the investigated compounds. The determined Km values ranged from 0.010 μM (CYP2D6, 4-MMA-NBOMe) to 13 μM (CYP2B6, 4-EA-NBOMe). All NBOMes were good substrates of CYP2C19 and CYP2D6 resulting in very low Km values in the nanomolar range. The main contributors to hepatic net clearance were CYP2D6 for 25B-NBOMe (69%), 25C-NBOMe (83%), 25I-NBOMe (61%), 3,4-DMA-NBOMe (89%) as well as for 4-EA-NBOMe (62%) and CYP2C19 for 4-MMA-NBOMe (64%). As more than one isoform was involved in the particular steps, the risk of harm associated with drug-drug interactions might be considered low. However, in cases where substances with high contributions from polymorphically expressed CYP2C19 and CYP2D6 are encountered, inter-individual variations in metabolism and excretion cannot be excluded.

KEYWORDS:

Michaelis-Menten kinetic; NBOMe; Relative activity factor; Substrate depletion approach

PMID:
29277574
DOI:
10.1016/j.toxlet.2017.12.017
[Indexed for MEDLINE]

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