Cytochrome P450 enzymes contribute to the metabolism of LSD to nor-LSD and 2-oxo-3-hydroxy-LSD: Implications for clinical LSD use

[Display omitted] In recent years, experimental research on lysergic acid diethylamide (LSD) in humans has gained new momentum. In humans, LSD is metabolized rapidly into several metabolites but knowledge of the involved metabolizing enzymes is limited. The aim of the current study was to identify t...

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Published in:Biochemical pharmacology 2019-06, Vol.164, p.129-138
Main Authors: Luethi, Dino, Hoener, Marius C., Krähenbühl, Stephan, Liechti, Matthias E., Duthaler, Urs
Format: Article
Language:English
Subjects:
2-Oxo-3-hydroxy-LSD
Animals
Cytochrome P-450 Enzyme System - metabolism
Cytochrome P450
Drug Interactions - physiology
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
HEK293 Cells
Humans
LSD
Lysergic Acid Diethylamide - analogs & derivatives
Lysergic Acid Diethylamide - metabolism
Lysergic Acid Diethylamide - pharmacology
Mice
Microsomal assay
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
NIH 3T3 Cells
Nor-LSD
Serotonin Receptor Agonists - metabolism
Serotonin Receptor Agonists - pharmacology
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Summary:[Display omitted] In recent years, experimental research on lysergic acid diethylamide (LSD) in humans has gained new momentum. In humans, LSD is metabolized rapidly into several metabolites but knowledge of the involved metabolizing enzymes is limited. The aim of the current study was to identify the cytochrome P450 (CYP) isoforms involved in the metabolism of LSD to 6-norlysergic acid diethylamide (nor-LSD) and 2-oxo-3-hydroxy-LSD (O-H-LSD) in vitro, in order to evaluate potential effects of enzyme polymorphisms or prescription drugs on LSD pharmacokinetics. Additionally, interactions of LSD and both metabolites with 5-hydroxytryptamine (5-HT) receptors were assessed. LSD was incubated with human liver microsomes over 4 h and the production of nor-LSD and O-H-LSD was quantified by liquid chromatography tandem mass spectrometry. Metabolism was inhibited by the addition of specific CYP inhibitors. Additionally, recombinant CYPs were used to verify the inhibition results obtained with microsomes and induction of metabolism was investigated in human hepatocyte-derived cells. Radioligand binding and calcium mobilization assays were used to determine 5-HT receptor affinities and activities, respectively. Human liver microsomes displayed minor metabolite formation (
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2019.04.013