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 journalArticle

12 Citations (Scopus)

Abstract

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
JournalXenobiotica
Volume41
Issue number10
DOIs
Publication statusPublished - Oct 2011

Fingerprint

Pharmacokinetics
Sex Characteristics
Rats
Liver
Metabolism
Microsomes
Biological Availability
Oral Administration
cilostazol
Cytochromes
Metabolites
Intravenous Administration
Small Intestine
Area Under Curve
Protein Isoforms
Perfusion

Keywords

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

ASJC Scopus subject areas

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

Cite this

Kamada, N., Yamada, K., Odomi, M., Mukai, T., Nishibayashi, T., Ogawara, K. I., ... Higaki, K. (2011). Sex differences in pharmacokinetics of cilostazol in rats. Xenobiotica, 41(10), 903-913. https://doi.org/10.3109/00498254.2011.590242

Sex differences in pharmacokinetics of cilostazol in rats. / Kamada, Naoki; Yamada, Keigo; Odomi, Masaaki; Mukai, Tadashi; Nishibayashi, Toru; Ogawara, Ken Ichi; Kimura, Toshikiro; Higaki, Kazutaka.

In: Xenobiotica, Vol. 41, No. 10, 10.2011, p. 903-913.

Research output: Contribution to journalArticle

Kamada, N, Yamada, K, Odomi, M, Mukai, T, Nishibayashi, T, Ogawara, KI, Kimura, T & Higaki, K 2011, 'Sex differences in pharmacokinetics of cilostazol in rats', Xenobiotica, vol. 41, no. 10, pp. 903-913. https://doi.org/10.3109/00498254.2011.590242
Kamada N, Yamada K, Odomi M, Mukai T, Nishibayashi T, Ogawara KI et al. Sex differences in pharmacokinetics of cilostazol in rats. Xenobiotica. 2011 Oct;41(10):903-913. https://doi.org/10.3109/00498254.2011.590242
Kamada, Naoki ; Yamada, Keigo ; Odomi, Masaaki ; Mukai, Tadashi ; Nishibayashi, Toru ; Ogawara, Ken Ichi ; Kimura, Toshikiro ; Higaki, Kazutaka. / Sex differences in pharmacokinetics of cilostazol in rats. In: Xenobiotica. 2011 ; Vol. 41, No. 10. pp. 903-913.
@article{a40173e68e22497989ab78a0ceb087fb,
title = "Sex differences in pharmacokinetics of cilostazol in rats",
abstract = "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.",
keywords = "Bioavailability, first-pass metabolism, gender, hepatic clearance, intestinal absorption, total body clearance",
author = "Naoki Kamada and Keigo Yamada and Masaaki Odomi and Tadashi Mukai and Toru Nishibayashi and Ogawara, {Ken Ichi} and Toshikiro Kimura and Kazutaka Higaki",
year = "2011",
month = "10",
doi = "10.3109/00498254.2011.590242",
language = "English",
volume = "41",
pages = "903--913",
journal = "Xenobiotica",
issn = "0049-8254",
publisher = "Informa Healthcare",
number = "10",

}

TY - JOUR

T1 - Sex differences in pharmacokinetics of cilostazol in rats

AU - Kamada, Naoki

AU - Yamada, Keigo

AU - Odomi, Masaaki

AU - Mukai, Tadashi

AU - Nishibayashi, Toru

AU - Ogawara, Ken Ichi

AU - Kimura, Toshikiro

AU - Higaki, Kazutaka

PY - 2011/10

Y1 - 2011/10

N2 - 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.

AB - 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.

KW - Bioavailability

KW - first-pass metabolism

KW - gender

KW - hepatic clearance

KW - intestinal absorption

KW - total body clearance

UR - http://www.scopus.com/inward/record.url?scp=80052890662&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052890662&partnerID=8YFLogxK

U2 - 10.3109/00498254.2011.590242

DO - 10.3109/00498254.2011.590242

M3 - Article

C2 - 21718207

AN - SCOPUS:80052890662

VL - 41

SP - 903

EP - 913

JO - Xenobiotica

JF - Xenobiotica

SN - 0049-8254

IS - 10

ER -