Abstract
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.
Footnotes
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Send reprint requests to: Amin A. Nomeir, Ph.D., Director, Exploratory Drug Metabolism, Department of Drug Metabolism and Pharmacokinetics, Mail Stop 2880, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033. E-mail:amin.nomeir{at}spcorp.com
- Abbreviations used are::
- HL
- human liver
- SCH 66712
- 5-fluoro-2-[4-[(2-phenyl-1H-imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine
- kinact
- maximal rate constant of inactivation
- P450
- cytochrome P450
- HPLC
- high-performance liquid chromatography
- GSH
- glutathione
- Received November 17, 2000.
- Accepted February 17, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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