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Xenobiotica
the fate of foreign compounds in biological systems
Volume 41, 2011 - Issue 10
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Animal Pharmacokinetics and Metabolism

Sex differences in pharmacokinetics of cilostazol in rats

, , , , , , & show all
Pages 903-913 | Received 17 Mar 2011, Accepted 18 May 2011, Published online: 01 Jul 2011
 

Abstract

  1. The pharmacokinetics of cilostazol was investigated after oral and intravenous administration in both male and female rats. After oral administration, area under serum concentration–time curve (AUC) was about 35-fold higher in female rats than in male rats, and absolute bioavailability was about 5.8-fold higher in female rats than in male rats.

  2. Total body clearance (CLtotal) for female rats was around one-sixth of that for male rats. In vivo hepatic clearance (CLh) calculated based on isolated liver perfusion studies was even higher than or around 90% of the in vivo CLtotal of cilostazol for female and male rats, respectively, indicating that cilostazol is mainly eliminated by the liver in both male and female rats.

  3. In vitro metabolism studies utilizing hepatic microsomes and recombinant cytochrome (CYP) isoforms clearly indicated that major metabolites of cilostazol were generated extensively with hepatic microsomes of male rats and that male-predominant CYP3A2 and male-specific CYP2C11 were mainly responsible for the hepatic metabolism of cilostazol. Therefore, the great sex differences in the pharmacokinetics of cilostazol were mainly attributed to the large difference in hepatic metabolism.

  4. Our experimental results also suggested that the substantial metabolism of cilostazol in the small intestine and its possible saturation would be responsible for dose-dependent bioavailability in both male and female rats.

Acknowledgements

The authors thank Chie Emoto, Ph.D. and Ken Umehara, Ph.D. for their support of the in vitro metabolism study.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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