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 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. 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.

Local Drug-Drug Interaction of Donepezil with Cilostazol at Breast Cancer Resistance Protein (ABCG2) Increases Drug Accumulation in Heart

“…Plasma total concentrations of cilostazol at the low and high doses were 8.54 and 16.7 mM, respectively, and the unbound fraction in rat plasma was about 1% (Kamada et al, 2011), so these doses are comparable with the unbound concentrations achievable at clinical doses in humans (1.35 to 2.7 mM, Interview form of cilostazol).…”

“…In the present study, we used female rats because there is a sex difference in the pharmacokinetics of cilostazol; females show higher plasma concentrations with a longer half-life (Kamada et al, 2011), which is useful for the current study.…”

“…In this study, observed plasma unbound concentrations of cilostazol at 3.5 hours after oral administration were 85.4 6 6.7 nM and 167 6 39 nM at doses of 100 and 500 mg/kg, respectively, using the reported plasma unbound fraction of 0.01 in rats (Kamada et al, 2011), and that of elacridar at 30 minutes after 1 mg/kg intravenous administration was 181 6 0.02 nM, using the plasma unbound fraction of 0.02 (Kallem et al, 2012). The IC 50 values of cilostazol for BCRP and P-glycoprotein were 130 nM and 12.7 mM, respectively (this study), and those of elacridar were 252 nM and 4 nM (Kwak et al, 2010), respectively.…”

Aspirin and Probenecid Inhibit Organic Anion Transporter 3–Mediated Renal Uptake of Cilostazol and Probenecid Induces Metabolism of Cilostazol in the Rat

“…In humans, cilostazol is metabolized to (Kim et al, 2009). In rats, the metabolism of cilostazol to OPC-13015 or OPC-13213 is mediated by CYP3A2 or CYP2C11 (Kamada et al, 2011). CYP3A2 and CYP2C11 expressed in rats are the most similar to CYP3A4 and CYP2C19 in humans (Bogaards et al, 2000;VanAlstine and Hough, 2011).…”

Effects of Chronic Treatment With Cilostazol, a Phosphodiesterase 3 Inhibitor, on Female Rat Bladder in a Partial Bladder Outlet Obstruction Model

“…In the present study, we examined a low dose (0.003% in feed) and a high dose (0.01% in feed) of cilostazol on the basis of prior reports, in which oral cilostazol administration to rats resulted in different Matsumoto S, et al, Effect of PDE3i treatment on female rat obstructed bladder -7 -blood concentrations between male and females rats with several ten-fold higher levels in female rats compared to male rats, and the doses of 0.03%, 0.1% and 0.3% were used in oral cilostazol administration to male rats [18][19][20][21].…”