TY - JOUR T1 - 2-Diethylaminoethyl-2,2-diphenylvalerate-HCl (SKF525A) Revisited: Comparative Cytochrome P450 Inhibition in Human Liver Microsomes by SKF525A, Its Metabolites, and SKF-Acid and SKF-Alcohol JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2539 LP - 2546 DO - 10.1124/dmd.108.023549 VL - 36 IS - 12 AU - Michael R. Franklin AU - Laura B. Hathaway Y1 - 2008/12/01 UR - http://dmd.aspetjournals.org/content/36/12/2539.abstract N2 - When incubated with human liver microsomes, 2-diethylaminoethyl-2,2-diphenylvalerate-HCl (SKF525A) undergoes cytochrome P450 (P450)-dependent oxidative N-deethylation to the secondary amine metabolite 2-ethylaminoethyl-2,2-diphenylvalerate (SKF8742). P450-selective inhibitors indicated CYP3As catalyzed this reaction, and the deethylation rate correlated best with the CYP3A activity across a range of human liver microsomes. SKF525A and its metabolite and primary amine analog all inhibited CYP2B6-, CYP2C9-, CYP2C19-, CYP2D6-, and CYP3A-selective reactions to varying degrees but had little effect on CYP1A2, CYP2A6, and CYP2E1 reactions. Only the inhibition of CYP3A showed major enhancement when the inhibitors were preincubated with NADPH-fortified microsomes, and the extent of metabolic intermediate (MI) complex formation approximated typical CYP3A content. Two “lost with time” SKF525A derivatives devoid of the ethylamine moiety, 2,2-diphenylpropylethanol (SKF-Alcohol) and 2,2-diphenylpropylacetic acid (SKF-Acid) did not form an MI complex and were identified as selective inhibitors of CYP2C9. Although without detectable metabolism, their CYP2C9 inhibition fitted best with a competitive mechanism. Thus, not all the human P450s are inhibited by SKF525A and related compounds, and the mechanisms contributing to those that are inhibited vary with the isoform. P450 MI-complex formation only seems to play a role with CYP3As. The American Society for Pharmacology and Experimental Therapeutics ER -