RT Journal Article
SR Electronic
T1 Identification of Cytochrome P450 Enzymes Involved in the Metabolism of the New Designer Drug 4′-Methyl-α-pyrrolidinobutyrophenone
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 163
OP 168
DO 10.1124/dmd.107.017293
VO 36
IS 1
A1 Frank T. Peters
A1 Markus R. Meyer
A1 Denis S. Theobald
A1 Hans H. Maurer
YR 2008
UL http://dmd.aspetjournals.org/content/36/1/163.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics