title: In vitro cytochrome P450 inhibition potential of methylenedioxy-derived designer drugs studied with a two-cocktail approach.
abstract: In vitro cytochrome P450 (CYP) inhibition assays are common approaches for testing the inhibition potential of drugs for predicting potential interactions. In contrast to marketed medicaments, drugs of abuse, particularly the so-called novel psychoactive substances, were not tested before distribution and consumption. Therefore, the inhibition potential of methylenedioxy-derived designer drugs (MDD) of different drug classes such as aminoindanes, amphetamines, benzofurans, cathinones, piperazines, pyrrolidinophenones, and tryptamines should be elucidated. The FDA-preferred test substrates, split in two cocktails, were incubated with pooled human liver microsomes and analysed after protein precipitation using LC-high-resolution-MS/MS. IC50 values were determined of MDD showing more than 50 % inhibition in the prescreening. Values were calculated by plotting the relative metabolite concentration formed over the logarithm of the inhibitor concentration. All MDD showed inhibition against CYP2D6 activity and most of them in the range of the clinically relevant CYP2D6 inhibitors quinidine and fluoxetine. In addition, the beta-keto compounds showed inhibition of the activity of CYP2B6, 5,6-MD-DALT of CYP1A2 and CYP3A, and MDAI of CYP2A6, all in the range of clinically relevant inhibitors. In summary, all MDD showed inhibition of the activity of CYP2D6, six of CYP1A2, three of CYP2A6, 13 of CYP2B6, two of CYP2C9, six of CYP2C19, one of CYP2E1, and six of CYP3A. These results showed that the CYP inhibition by MDD might be clinically relevant, but further studies are needed for final conclusions.
authors.affiliation: Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, 66421, Homburg, Saar, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Dinger
authors.affiliation: Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, 66421, Homburg, Saar, Germany.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Meyer
authors.affiliation: Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, 66421, Homburg, Saar, Germany. hans.maurer@uks.eu.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Maurer
mesh_terms: D015104:3,4-Methylenedioxyamphetamine / Q000493:pharmacokinetics / Q000633:toxicity; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D015198:Designer Drugs / Q000493:pharmacokinetics* / Q000633:toxicity*; D004347:Drug Interactions; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000493:pharmacokinetics / Q000633:toxicity; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D015198:Designer Drugs; D010880:Piperidines; C067455:2-methyl-1,1-diphenyl-3-(1-piperidinyl)-1-propanol; D015104:3,4-Methylenedioxyamphetamine; C043429:1-(2,3-methylenedioxyphenyl)-2-aminopropane
keywords: CYP inhibition; IC50 value; LC-HR-MS/MS; Methylenedioxy-derived designer drugs