title: A non-acidic sulfaphenazole analog demonstrating high intrinsic clearance and selectivity by canine CYP2C21.
abstract: 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 K(m). Furthermore, CYP2C21 demonstrated selectivity for formation of the benzylic hydroxylation product and a high estimated f(m,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.
authors.affiliation: Pfizer Animal Health, Veterinary Medicine Research and Development, Metabolism & Safety, Kalamazoo, MI 49001, USA. charles.w.locuson@pfizer.com
authors.forename: Charles W
authors.initials: CW
authors.lastname: Locuson
authors.forename: Josh F
authors.initials: JF
authors.lastname: Alfaro
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Zaya
authors.forename: Denis
authors.initials: D
authors.lastname: Billen
authors.forename: Julie A
authors.initials: JA
authors.lastname: White
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Jones
mesh_terms: D000818:Animals; D001711:Biotransformation; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003640:Dealkylation; D004285:Dogs; D006900:Hydroxylation; D007700:Kinetics; D008657:Metabolic Clearance Rate; D008745:Methylation; D015335:Molecular Probes; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D013426:Sulfaphenazole / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D015335:Molecular Probes; D011994:Recombinant Proteins; D013426:Sulfaphenazole; D003577:Cytochrome P-450 Enzyme System; C084930:cytochrome P-450 2C2