Skip to main content

Cilostazol Pharmacokinetics after Single and Multiple Oral Doses in Healthy Males and Patients with Intermittent Claudication Resulting from Peripheral Arterial Disease

Clinical Pharmacokinetics volume 37, pages 1–11 (1999)Cite this article

Abstract

Objective

To study the pharmacokinetics of cilostazol following single oral administration of 50 to 200mg in healthy young males, and after repeated oral administration of 100mg every 12 hours to patients with peripheral arterial disease (PAD).

Design

The healthy male single dose study was a single-centre, randomised sequence, open-label, incomplete block, 3-period, 4-treatment, crossover design. The patient study was a single-centre, multiple dose, open-label study.

Study Participants

20 healthy nonsmoking male volunteers were enrolled and successfully completed the single dose study. 26 patients (21 males, 5 females) with intermittent claudication resulting from PAD were enrolled and completed the single/multiple dose study.

Main Outcome Measures

Noncompartmental pharmacokinetic parameters, the area under the plasma concentration-time curve from zero to the time of last measurable plasma concentration, and maximum plasma concentration.

Results

Peak plasma concentrations of cilostazol occurred about 3 hours after drug administration and then declined biexponentially with concentrations detectable (>20 μg/L) in the plasma for at least 36 hours postdose. The apparent elimination half-life of cilostazol (approximately 11 hours) was similar after a single dose or after multiple doses, with steady state being reached within 4 days. Cilostazol accumulated 1.7-fold following multiple dose administration. The apparent volume of distribution (Vz/F; 2.76 L/kg) suggested extensive distribution of cilostazol in the tissues. The oral clearance of cilostazol (CL/F; 0.18 L/h/kg) was much lower than liver blood flow, indicating a low extraction ratio drug, and hence low probability of a significant first-pass effect. None of the administered doses were recovered in the urine as unchanged cilostazol, suggesting that metabolism, rather than urinary excretion, is the major elimination route. Following single oral doses of 50 to 200mg, the plasma concentrations of cilostazol and its metabolites increased less than proportionally to the dose. The pharmacokinetics of cilostazol in normal healthy volunteers are predictive of those in patients with PAD. Single oral doses of 50 to 200mg cilostazol as well as 100mg cilostazol every 12 hours were well tolerated.

Conclusion

The plasma concentration of cilostazol and its metabolites increased less than proportionally with increasing doses. The relatively low plasma clearance and high volume of distribution of cilostazol suggest a low first-pass effect and extensive distribution. The pharmacokinetics of cilostazol in normal volunteers is predictive of that in patients with PAD. Cilostazol was well tolerated in healthy volunteers and patients with intermittent claudication resulting from PAD.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

49,54 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Kimura Y, Tani T, Kanbe T, et al. Effect of cilostazol on platelet aggregation and experimental thrombosis. Arzneimittelforschung 1985; 35(7A): 1144–9.

    PubMed  CAS  Google Scholar 

  2. Kohriyama T, Tanaka E, Katayama S, et al. Antiplatelet therapy in patients with cerebral thrombosis at the chronic phase-assessment of its effect on coagulation and fibrinolytic parameters. Rinsho Shinkeigaku 1994; 34(8): 771–6.

    PubMed  CAS  Google Scholar 

  3. Uchikawa T, Murakami T, Furukawa H. Effects of the antiplatelet agent cilostazol on peripheral vascular disease in patients with diabetes mellitus. Arzneimittelforschung 1992; 42(3): 322–4.

    PubMed  CAS  Google Scholar 

  4. Okuda Y, Mizutani M, Ikegami T, et al. Hemodynamic effects of cilostazol on peripheral artery in patients with diabetic nephropathy. Arzneimittelforschung 1992; 42(4): 540–2.

    PubMed  CAS  Google Scholar 

  5. Tsuchikane E, Katoh O, Sumitsuji S, et al. Impact of cilostazol on intimai proliferation following directional coronary atherectomy: a prospective randomized trial. J Am Coll Cardiol 1997; 29(2 Suppl. A): 397A.

    Google Scholar 

  6. Suehiro A, Sugimoto Y, Masuda H, et al. A study of the effects of cilostazol on platelet function and serum lipids in patients with diabetes mellitus. Curr Ther Res 1993; 54(5): 553–61.

    Article  Google Scholar 

  7. Elam MB, Heckman J, Crouse JR, et al. Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication. Arterioscler Thromb Vasc Biol 1998; 18(12): 1942–7.

    PubMed  Article  CAS  Google Scholar 

  8. Strandness D, Eugene MD, Braunwald E, et al., editors. Vascular diseases of the extremities. Principles of internal medicine. New York: McGraw-Hill, 1987: 1040–6.

    Google Scholar 

  9. Bramer SL, Forbes WP. Relative bioavailability and effects of a high fat meal on single dose cilostazol pharmacokinetics. Clin Pharmacokinet 1999; 37 Suppl. 2: 13–23.

    PubMed  Article  CAS  Google Scholar 

  10. Fu CJ, Tata PNV, Bramer SL. Simultaneous quantitative determination of cilostazol and its metabolites in plasma by high performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1999; 728(2): 251–62.

    PubMed  Article  CAS  Google Scholar 

  11. Heitkamp JJ, Tata PNV, Li Y-X, et al. Simultaneous LC-MS/MS determination of cilostazol (OPC-13013) and three of its principal metabolites in human plasma. Abstract presented at American Association of Pharmaceutical Scientists; 1998 Novl San Francisco, 1998.

  12. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, 1982: 332–6.

    Google Scholar 

  13. Zar JH. Power of statistical testing: hypotheses about means. Am Laborat 1981; 13(6): 102–7.

    Google Scholar 

  14. Suri A, Forbes WP, Bramer SL. Pharmacokinetics of multiple-dose oral cilostazol in middle-aged and elderly men and women. J Clin Pharmacol 1998 Feb; 38: 144–50.

    PubMed  CAS  Google Scholar 

  15. Abbas R, Chow CP, Browder NJ, et al. In vitro metabolism and interaction of cilostazol with human hepatic cytochrome P450 isoforms. Hum Exp Toxicol. In press.

  16. Wilding JR, Coupe AJ, Davis SS. The role of γ-scintigraphy in oral drug delivery. Adv Drug Deliv Rev 1991; 7: 87–117.

    Article  CAS  Google Scholar 

  17. Podczek F, Newton JM, Yuen K. The description of gastrointestinal transit of pellets assessed by gamma scintigraphy using statistical moments. Pharm Res 1995; 12(3): 376–9.

    Article  Google Scholar 

  18. Adkin DA, Gowland P, Spiller RC, et al. The effects of pharmaceutical excipients on small intestinal transit. Br J Clin Pharmacol 1995; 39(4): 381–7.

    PubMed  Article  CAS  Google Scholar 

  19. Mallikaarjun S, Mico BA, Forbes WP, et al, Pharmacokinetics of cilostazol in renal insufficiency. [abstract no. 3140]. American Association of Pharmaceutical Scientists Annual Meeting; 1997 Nov 2–6; Boston. Pharm Res 1997; 14 Suppl. 11: S512.

    Google Scholar 

  20. Bramer SL, Tata PNV, Mallikaarjun S, et al. Disposition of 14C-Cilostazol after single dose administration to healthy human subjects [abstract no. 3452]. American Association of Pharmaceutical Scientists Annual Meeting; 1997 Nov 2–6; Boston. Pharm Res 1997; 14 Suppl. 11: S612.

    Google Scholar 

Download references

Author information

Affiliations

  1. Otsuka America Pharmaceutical, Inc., Rockville, Maryland, USA

    Steven L. Bramer, William P. Forbes & Suresh Mallikaarjun

Authors
  1. Steven L. Bramer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William P. Forbes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suresh Mallikaarjun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven L. Bramer.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bramer, S.L., Forbes, W.P. & Mallikaarjun, S. Cilostazol Pharmacokinetics after Single and Multiple Oral Doses in Healthy Males and Patients with Intermittent Claudication Resulting from Peripheral Arterial Disease. Clin Pharmacokinet 37, 1–11 (1999). https://doi.org/10.2165/00003088-199937002-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-199937002-00001

Keywords

  • Adis International Limited
  • Peripheral Arterial Disease
  • Normal Volunteer
  • Cilostazol
  • Intermittent Claudication