A Non-acidic Sulfaphenazole Analog Demonstrating High Intrinsic Clearance and Selectivity by Canine CYP2C21
Charles W. Locuson,
Josh F. Alfaro,
Matthew J. Zaya,
Julie A. White,
Jeffrey P. Jones.
In contrast to human CYP2C9, non-human CYP2C enzymes do not appear to preferentially bind and metabolize anionic drugs. Using analogs of sulfaphenazole, the effect of an acidic sulfonamide group on apparent affinity and turnover rates was characterized with canine CYP2C21. Blocking the sulfonamide with a methyl group increased the intrinsic clearance by CYP2C21 > 100-fold and decreased Km. Furthermore, CYP2C21 demonstrated selectivity for formation of the benzylic hydroxylation product and a high estimated fm,CYP value. The findings suggest that canine CYP2C21, unlike human CYP2C9, does not derive ligand binding affinity from an anion binding interaction with sulfaphenazole analogs.
Keywords: CYP2C, cytochrome P450, dog metabolism, probe substrate, recombinant P450, sulfaphenazole, CYP2C92, Formic acid, oxidoreductase, Tandem mass spectrometry
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