PT  - JOURNAL ARTICLE
AU  - Jairam R. Palamanda
AU  - Christopher N. Casciano
AU  - Laura A. Norton
AU  - Robert P. Clement
AU  - Leonard V. Favreau
AU  - Chin-chung Lin
AU  - Amin A. Nomeir
TI  - Mechanism-Based Inactivation of CYP2D6 by 5-Fluoro-2-[4-[(2-phenyl-1<em>H</em>-imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine
DP  - 2001 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 863--867
VI  - 29
IP  - 6
4099  - http://dmd.aspetjournals.org/content/29/6/863.short
4100  - http://dmd.aspetjournals.org/content/29/6/863.full
SO  - Drug Metab Dispos2001 Jun 01; 29
AB  - SCH 66712 [5-fluoro-2-[4-[(2-phenyl-1H-imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine] caused a time- and NADPH-dependent loss of CYP2D6 activity. The inactivation of human liver (HL) microsomal dextromethorphanO-demethylase activity, a prototype marker for CYP2D6, was characterized by a K I of 4.8 μM and a maximal rate constant of inactivation (k inact) of 0.14 min−1. The inactivation of the recombinant CYP2D6 in Supersomes (r-CYP2D6) was characterized by a K I of 0.55 μM and ak inact of 0.32 min−1. Extensive dialysis of the SCH 66712-inhibited enzyme failed to restore the activity to control levels (dialyzed reaction mixture lacking SCH 66712) for both HL microsomes and r-CYP2D6. Addition of glutathione, superoxide dismutase, or mannitol to the reaction mixture failed to protect CYP2D6 against SCH 66712-NADPH-catalyzed inactivation. Addition of quinidine, a reversible inhibitor of CYP2D6, to a preincubation mixture consisting of SCH 66712, HL microsomes, or Supersomes and NADPH partially protected CYP2D6 from inactivation. SCH 66712 also inhibited HL microsomal CYP3A4, CYP2C9, and CYP2C19; however, the concentrations required to inhibit those isoforms were 5- to 10-fold higher than those required to inhibit CYP2D6. These results demonstrate that SCH 66712 is a potent and fairly selective mechanism-based inhibitor of CYP2D6. The American Society for Pharmacology and Experimental Therapeutics