Mechanism Based Inactivation of Cytochrome P450 3A4 by 5-Fluoro-2-[4-[(2-phenyl-1H- imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine
Bolles, Amanda K.
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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 previously been confirmed as a mechanism based inactivator (MBI) of CYP2D6 and data suggested it could also 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. Inactivation 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. For the inactivation of CYP3A4 by SCH66712 the maximal rate constant of inactivation (kinact) was determined to be 0.036 min-1, the inactivator concentration required for half maximum inactivation (KI) was determined to be 2.70 μM, and the efficiency (kinact/KI) of inactivation determined to be 0.013 μM/min. The partition ratio was determined to be 11. suggesting SCH66712 is a potent MBI of CYP3A4. The compilation of these results confirm that SCH66712 is a potent and efficient mechanism based inactivator of CYP3A4.