5‐Fluoro‐2‐[4‐[(2‐phenyl‐1H‐imidazol‐5‐yl)methyl]‐1 piperazinyl]pyrimidine is a mechanism based inactivator of CYP3A4 (615.6)

Abstract

Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of over fifty percent of pharmaceutical drugs on the market today. Inhibition of CYP3A4 can lead to adverse drug‐drug interactions. 5‐Fluoro‐2‐[4‐[(2‐phenyl‐1H‐imidazol‐5‐yl)methyl]‐1‐piperazinyl]pyrimidine (SCH66712) has been previously identified as a mechanism based inactivator (MBI) of CYP2D6 and preliminarily data also suggested it could be an inactivator of CYP3A4 [Palamanda, Casciano, Norton, Clement, Favreau, Lin, Nomeir (2001) Drug Metab Dispos 29, 863‐867]. In the current study SCH66712 was shown to be an MBI of CYP3A4. Inhibition of CYP3A4 by SCH66712 was determined to be concentration‐, time‐ and NADPH‐dependent. In addition, inactivation of CYP3A4 by SCH66712 was shown to be unaffected by the presence of electrophile scavengers. SCH66712 displays type II binding to CYP3A4 with a spectral binding constant (Ks) of 43 ± 2 μM. The partition ratio was determined to be 11, suggesting SCH66712 is a potent MBI of CYP3A4. Analysis of possible mechanism of inactivation are also described.Grant Funding Source: Supported by NIH 1R15‐GM086767‐02