Sex differences in pharmacokinetics of cilostazol in rats

Naoki Kamada, Keigo Yamada, Masaaki Odomi, Tadashi Mukai, Toru Nishibayashi, Ken-ichi Ogawara, Toshikiro Kimura, Kazutaka Higaki

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


The pharmacokinetics of cilostazol was investigated after oral and intravenous administration in both male and female rats. After oral administration, area under serum concentrationtime 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. Total body clearance (CL total) for female rats was around one-sixth of that for male rats. In vivo hepatic clearance (CL h) calculated based on isolated liver perfusion studies was even higher than or around 90% of the in vivo CL total of cilostazol for female and male rats, respectively, indicating that cilostazol is mainly eliminated by the liver in both male and female rats. 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. 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.

Original languageEnglish
Pages (from-to)903-913
Number of pages11
Issue number10
Publication statusPublished - Oct 2011


  • Bioavailability
  • first-pass metabolism
  • gender
  • hepatic clearance
  • intestinal absorption
  • total body clearance

ASJC Scopus subject areas

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Health, Toxicology and Mutagenesis


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