Received for publication June 18, 2007.
Revised October 1, 2007.
Accepted for publication October 22, 2007.

Identification of Cytochrome P450 Enzymes Involved in the Metabolism of the New Designer Drug 4'-Methyl--pyrrolidinobutyrophenone (MPBP)

Abstract

The involvement of human hepatic cytochrome P450 (CYP) isoenzymes in the metabolism of the new designer drug 4'-methyl--pyrrolidinobutyrophenone (MPBP) to 4'-(hydroxymethyl)--pyrrolidinobutyrophenone (HO-MPBP) was studied using insect cell microsomes with cDNA-expressed human CYPs 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 -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 to pooled HLM, respectively. From these data, it can be concluded that polymorphically expressed CYP2D6 is mainly responsible for MPBP hydroxylation.

Key words: CYP1A, CYP2C, CYP2D, cytochrome P450 catalyzed oxidations, cytochrome P450 isoforms, human CYP enzymes, metabolite kinetics, polymorphisms, toxicology