RT Journal Article SR Electronic T1 Effect of Quinidine on the 10-Hydroxylation of R-Warfarin: Species Differences and Clearance Projection JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 307 OP 314 DO 10.1124/jpet.104.069955 VO 311 IS 1 A1 Qing Chen A1 Eugene Tan A1 John R. Strauss A1 Zhoupeng Zhang A1 Judith E. Fenyk-Melody A1 Catherine Booth-Genthe A1 Thomas H. Rushmore A1 Ralph A. Stearns A1 David C. Evans A1 Thomas A. Baillie A1 Wei Tang YR 2004 UL http://jpet.aspetjournals.org/content/311/1/307.abstract AB Stimulation by quinidine of warfarin metabolism in vitro was first demonstrated with liver microsomal preparations. We report herein that this drug interaction is reproducible in an animal model but that it exhibits profound species differences. Thus, using rabbit liver microsomes and a kinetic model incorporating two binding sites, the hepatic intrinsic clearance of R-warfarin via the 10-hydroxylation pathway (CLintW) was projected to be 6 ± 1 and 128 ± 51 μl/min/g liver, respectively, in the absence and presence of 21 μM unbound quinidine. These estimates were consistent with the results from studies in which rabbit livers (n = 5) were perfused in situ with R-warfarin or R-warfarin plus quinidine. The CLintW increased from 7 ± 3 to 156 ± 106 μl/min/g liver after increasing the hepatic exposure of unbound quinidine from 0 to 21 μM. In contrast, when liver microsomes or intact livers from rats were examined, R-warfarin metabolism was inhibited by quinidine, the CLintW decreasing to 26% of the control value after exposure of perfused rat livers (n = 5) to 22 μM unbound quinidine. The third example involved monkey liver microsomes, in which the rate of 10-hydroxylation of R-warfarin was little affected in the presence of quinidine (<2-fold increase). In all three species, the 10-hydroxylation of R-warfarin was catalyzed primarily by members of CYP3A, based on immuno- and chemical inhibition analyses. These findings not only highlight the variability of drug interactions among different species but also suggest that changes in hepatic clearance resulting from stimulation of cytochrome P450 activity may be projected based on estimates generated from corresponding liver microsomal preparations. The American Society for Pharmacology and Experimental Therapeutics