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First published on May 26, 2004; DOI: 10.1124/jpet.104.069955

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Received for publication April 16, 2004.
Revised May 25, 2004.
Accepted for publication May 26, 2004.

Effect of quinidine on the 10-hydroxylation of R-warfarin: Species difference and clearance projection

Qing Chen 1, Eugene Tan 1, John Strauss 1, Zhoupeng Zhang 1, Judith Fenyk-Melody 1, Catherine Booth-Genthe 1, Thomas Rushmore 1, Ralph Stearns 1, David Evans 1, Thomas Baillie 1, Wei Tang 2*

1 Merck Research Laboratories 2 Merck & Co.

* Address correspondence to: E-mail: wei_tang{at}merck.com

Abstract

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 following exposure of perfused rat livers (n=5) to 22 µM unbound quinidine. The third example involving 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 of interest, the 10-hydroxylation of R-warfarin was catalyzed primarily by members of CYP3A, based on immuno- and chemical inhibition analyses. These findings highlight the variability of drug interactions among different species, but also suggest that changes in hepatic clearance resulting from stimulation of CYP activity may be projected based on estimates generated from corresponding liver microsomal preparations.


Key words: clearance projection, cytochrome P450 3A4, drug interaction, quinidine, species differences, warfarin


This article has been cited by other articles:


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[Abstract] [Full Text] [PDF]


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