Premium
SCH 66712 and EMTPP are the First Potent Mechanism‐Based Inactivators of Both Human CYP2D6 and CYP3A4
Author(s) -
Fujiwara Rina,
Bolles Amanda,
Briggs Erran,
Nomeir Amin,
Furge Laura
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.716.11
Subject(s) - cyp3a4 , chemistry , enzyme , cyp2d6 , stereochemistry , cytochrome p450 , metabolite , imidazole , drug metabolism , isozyme , trifluoromethyl , heme , biochemistry , organic chemistry , alkyl
Cytochrome P450s (CYPs) are heme‐containing enzymes that metabolize small organic molecules including drugs. CYP3A4 and CYP2D6 are responsible for more than 70% of pharmaceutical drug metabolism and inactivation of these enzymes can lead to drug‐drug interactions. The substituted imidazole compounds, 5‐fluoro‐2‐[4‐[(2‐phenyl‐1H‐imidazol‐5‐yl)methyl]‐1‐piperazinyl]pyrimidine (SCH 66712) and 1‐[(2‐ethyl‐4‐methyl‐1H‐imidazol‐5‐yl)methyl]‐4‐[4‐(trifluoromethyl)‐2‐pyridinyl]piperazine (EMTPP), have been previously identified as mechanism‐based inactivators (MBIs) of CYP2D6. The current study shows SCH 66712 and EMTPP are also MBIs of CYP3A4. The partition ratios for SCH 66712 and EMTPP were 11 and 94, respectively. The rates of inactivation, k inact , and inhibition constant, K i ,were 0.21 min ‐1 and 1.6 µM for SCH 66712, and 0.046 min ‐1 and 11.7 µM for EMTPP, respectively. Whole protein MS analysis was consistent with a binding stoichiometry of 1:1 for both MBIs on CYP3A4 apoprotein. To determine the site of modification of the enzymes, MS analysis of digested peptides of inactivated enzymes was performed. Additionally, inactivation mechanisms of enzymes by possible electrophiles of SCH 66712 and EMTPP are proposed based in part on metabolite studies (Support: NIH 1R15‐GM086767‐02).