title: Identification of cytochrome P450 enzymes involved in the metabolism of the new designer drug 4'-methyl-alpha-pyrrolidinobutyrophenone.
abstract: The involvement of human hepatic cytochrome P450 (P450) isoenzymes in the metabolism of the new designer drug 4'-methyl-alpha-pyrrolidinobutyrophenone (MPBP) to 4'-(hydroxymethyl)-alpha-pyrrolidinobutyrophenone (HO-MPBP) was studied using insect cell microsomes with cDNA-expressed human P450s and human liver microsomes (HLM). Incubation samples were analyzed by liquid chromatography-mass spectrometry. Only CYP2D6, CYP2C19, and CYP1A2 were capable of catalyzing MPBP 4'-hydroxylation. According to the relative activity factor approach, these enzymes accounted for 54, 30, and 16% of net clearance. At 1 microM MPBP, the chemical inhibitors quinidine (CYP2D6), fluconazole (CYP2C19), and alpha-naphthoflavone (CYP1A2) reduced metabolite formation in pooled HLM by 83, 53, and 47%, respectively, and at 50 microM MPBP by 41, 47, and 45%, respectively. In experiments with HLM from CYP2D6 and CYP2C19 poor metabolizers, HO-MPBP formation was found to be 78 and 79% lower in comparison with pooled HLM, respectively. From these data, it can be concluded that polymorphically expressed CYP2D6 is mainly responsible for MPBP hydroxylation.
authors.affiliation: Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Building 46, D-66421 Homburg (Saar), Germany. frank.peters@uniklinikum-saarland.de
authors.forename: Frank T
authors.initials: FT
authors.lastname: Peters
authors.forename: Markus R
authors.initials: MR
authors.lastname: Meyer
authors.forename: Denis S
authors.initials: DS
authors.lastname: Theobald
authors.forename: Hans H
authors.initials: HH
authors.lastname: Maurer
mesh_terms: D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D002090:Butyrophenones / Q000378:metabolism* / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D015198:Designer Drugs / Q000378:metabolism* / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005822:Genetic Vectors; D006801:Humans; D006900:Hydroxylation; D007313:Insecta / Q000235:genetics; D007527:Isoenzymes; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000201:enzymology*; D011759:Pyrrolidines / Q000378:metabolism* / Q000493:pharmacokinetics; D014162:Transfection
chemical_list: C504661:4'-methyl-alpha-pyrrolidinobutyrophenone; D002090:Butyrophenones; D065607:Cytochrome P-450 Enzyme Inhibitors; D015198:Designer Drugs; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011759:Pyrrolidines; D003577:Cytochrome P-450 Enzyme System