Drug Metab Dispos. 2001 Jun;29(6):863-7.  

Mechanism-based inactivation of CYP2D6 by
5-fluoro-2-[4-[(2-phenyl-1H-imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine.

Palamanda JR, Casciano CN, Norton LA, Clement RP, Favreau LV, Lin C, Nomeir AA.

Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research
Institute, Kenilworth, New Jersey 07033, USA.

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 dextromethorphan O-demethylase activity, a prototype
marker for CYP2D6, was characterized by a K(I) of 4.8 microM 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
microM and a k(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.

PMID: 11353755 [PubMed - indexed for MEDLINE]