Abstract
The involvement of human hepatic cytochrome P450 (P450) isoenzymes in the metabolism of the new designer drug 4′-methyl-α-pyrrolidinobutyrophenone (MPBP) to 4′-(hydroxymethyl)-α-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 μM MPBP, the chemical inhibitors quinidine (CYP2D6), fluconazole (CYP2C19), and α-naphthoflavone (CYP1A2) reduced metabolite formation in pooled HLM by 83, 53, and 47%, respectively, and at 50 μM 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.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.017293.
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ABBREVIATIONS: P450, cytochrome P450; MPBP, 4′-methyl-α-pyrrolidinobutyrophenone; MPPP, 4′-methyl-α-pyrrolidinopropiophenone; MPHP, 4′-methyl-α-pyrrolidinohexanophenone; MDPPP, 3′,4′-methylenedioxy-α-pyrrolidinopropiophenone; PVP, α-pyrrolidinovalerophenone; HO-MPBP, 4′-hydroxymethyl-α-pyrrolidinobutyrophenone; ICM, insect cell microsomes; pHLM, pooled human liver microsomes; PMD6 HLM, single donor human liver microsomes from donors with poor metabolizer genotype for CYP2D6; PMC19 HLM, single donor human liver microsomes from donors with poor metabolizer genotype for CYP2C19; RAF, relative activity factor; TR, turnover rates; PS, probe substrate; LC-MS, liquid chromatography-mass spectrometry; APCI, atmospheric pressure chemical ionization.
- Received June 18, 2007.
- Accepted October 22, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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Identification of Cytochrome P450 Enzymes Involved in the Metabolism of the New Designer Drug 4′-Methyl-α-pyrrolidinobutyrophenone
