Skip to main content
Log in

Pharmacokinetic drug interaction between gemfibrozil and sitagliptin in healthy Indian male volunteers

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To study the impact of gemfibrozil co-administration on the pharmacokinetics of sitagliptin in healthy Indian male volunteers.

Methods

A randomized open label two-period crossover study involving 12 healthy Indian male volunteers was conducted at a single center. In each phase, the volunteers were administered sitagliptin as 100 mg tablets, either alone or co-administered with gemfibrozil as 600 mg tablets twice daily for 3 days. There was a 2-week washout period between phases. The venous blood samples were serially collected at 0–12 h post-dose, and plasma concentrations of the study drugs were estimated by a validated high-performance liquid chromatography-ultraviolet method.

Results

Relative to the administration of sitagliptin alone, co-administration with gemfibrozil increased the AUC0-12 (2,167 ± 82.9 vs. 2,970 ± 76.4 ng h/ml; p < 0.0001), AUC0-∞ (3,621 ± 222.5 vs. 5,574 ± 249.6 ng h/ml; p < 0.0002), Cmax (282.9 ± 7.7 vs. 344.1 ± 5.9 ng/ml; p < 0.0001), and t½ (7.4 ± 0.6 vs. 10 ± 0.6 h; p = 0.0076) to statistically significant levels. The interindividual differences in the pharmacokinetic parameters of sitagliptin were found to be within acceptable limits (coefficient of variation <20%). No adverse drug events associated with sitagliptin occurred in the subjects during the study period.

Conclusion

Although the bioavailability of sitagliptin was increased by 54% when co-administered with gemfibrozil, this interaction may not have any clinical significance as sitagliptin has a wide therapeutic index. Hence, in clinical practice, sitagliptin as 100 mg tablets and gemfibrozil as 600 mg tablets may be co-prescribed without much threat of sitagliptin toxicity. However, these results may not hold if the dose of sitagliptin is increased or if is co-prescribed with other antidiabetic drugs and/or cytochrome P450 2C8/human organic anion transporter-3 inhibitors. Further studies are needed to confirm these results in patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Zerilli T, Pyon EY (2007) Sitagliptin phosphate: a DPP-4 inhibitor for the treatment of type 2 diabetes mellitus. Clin Ther 29:2614–2634

    Article  PubMed  CAS  Google Scholar 

  2. Ahrén B (2007) DPP-4 inhibitors. Best Pract Res Clin Endocrinol Metab 21:517–533

    Article  PubMed  Google Scholar 

  3. Ahrén B (2007) Dipeptidyl peptidase-4 inhibitors: clinical data and clinical implications. Diabetes Care 30:1344–1350

    Article  PubMed  Google Scholar 

  4. Ahrén B (2009) Clinical results of treating type 2 diabetic patients with sitagliptin, vildagliptin or saxagliptin—diabetes control and potential adverse events. Best Pract Res Clin Endocrinol Metab 23:487–498

    Article  PubMed  Google Scholar 

  5. Merck (2006) Highlights of prescribing information JANUVIA. Available at: http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf. Accessed 15 June 2010

  6. Vincent SH, Reed JR, Bergman AJ, Elmore CS, Zhu B, Shiyao Xu et al (2007) Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C] sitagliptin in humans. Drug Metab Dispos 35:533–538

    Article  PubMed  CAS  Google Scholar 

  7. Xiao-Yan C et al (2007) Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1 and multidrug resistance P-glycoprotein. JPET 321:673–683

    Article  Google Scholar 

  8. Pfizer (2008) LOPID (package insert). Available at: www.pfizer.com/files/products/uspi_lopid.pdf. Accessed 10 June 2010

  9. Nakagomi-Hagihara R, Nakai D, Tokui T (2007) Inhibition of human organic anion transporter 3 mediated pravastatin transport by gemfibrozil and the metabolites in humans. Xenobiotica 37:416–426

    Article  PubMed  CAS  Google Scholar 

  10. Honkalammi J, Niemi M, Neuvonen PJ, Backman JT (2011) Mechanism-based inactivation of CYP2C8 by gemfibrozil occurs rapidly in humans. Clin Pharmacol Ther 89:579–586

    Article  PubMed  CAS  Google Scholar 

  11. Universal precautions for blood collection. http://www.who.int/injection_safety/toolbox/docs/AM_HCW_Safety. Accessed 2 Dec 2010

  12. Yong Zhanga, Meirong Huoa, Jianping Zhoua, Shaofei Xie (2010) PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Method Programs Biomed 99:306–314

  13. Zhang L, Zhang YD, Zhao P, Huang SM (2009) Predicting drug–drug Interactions: an FDA perspective. AAPS J 11:300–306

    Article  PubMed  CAS  Google Scholar 

  14. Pathak R, Bridgeman MB (2010) Dipeptidyl peptidase-4 (DPP-4) inhibitors in the management of diabetes. Pharm Therapeut J 35:509–513

    Google Scholar 

  15. Krishna R, Bergman A, Larson P, Cote J, Lasseter K, Dilzer S et al (2007) Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects. J Clin Pharmacol 47:165–174

    Article  PubMed  CAS  Google Scholar 

  16. Bergman AJ, Stevens C, Zhou YanYan, Yi B, Laethem M, De Smet M et al (2006) Pharmacokinetic and pharmacodynamics properties of multiple oral doses of Sitagliptin, a dipeptidyl peptidase 4 inhibitor: a double-blind, randomized, placebo-controlled studies in healthy subjects. Clin Ther 28:55–72

    Article  PubMed  CAS  Google Scholar 

  17. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H (2006) Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 49:2564–2571

    Article  PubMed  CAS  Google Scholar 

  18. Alba M, Sheng D, Guan Y, Williams-Herman D, Larson P, Sachs JR, Thornberry N, Herman G, Kaufman KD, Goldstein BJ (2009) Sitagliptin 100 mg daily effect on DPP-4 inhibition and compound-specific glycemic improvement. Curr Med Res Opin 25:2507–2514

    Article  PubMed  CAS  Google Scholar 

  19. Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M et al (2005) Pharmacokinetics and pharmacodynamics of Sitagliptin an inhibitor of dipeptidyl peptidase 4, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther 78:675–688

    Article  PubMed  CAS  Google Scholar 

  20. Migoyal EM, Stevens CH, Bergman AJ, Luo Wl, Lasseter KC, Dilzer SC et al (2009) Effect of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin. Can J Clin Pharmcol 16:165–170

    Google Scholar 

  21. Bergman AJ, Cote J, Bingming TM, Swan SK, Smith W et al (2007) Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care 30:1862–1864

    Article  PubMed  CAS  Google Scholar 

  22. Vilsboll T. Combination therapy with sitagliptin and metformin for type 2 diabetes: chemistry & pharmacokinetics of sitagliptin. Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. Available at: http://www.medscape.com/viewarticle/584860_2. Accessed 21 Apr 2010

Download references

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Arun K. P..

Rights and permissions

Reprints and permissions

About this article

Cite this article

K. P., A., Meda, V.S., Kucherlapati, V.S.P.R. et al. Pharmacokinetic drug interaction between gemfibrozil and sitagliptin in healthy Indian male volunteers. Eur J Clin Pharmacol 68, 709–714 (2012). https://doi.org/10.1007/s00228-011-1177-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-011-1177-2

Keywords

Navigation