Skip to main content
SpringerLink
Log in

The influence of piperine on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy volunteers

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

Abstract

Purpose

Piperine (PIP) has been found to inhibit P-glycoprotein (P-gp) function in rats, suggesting that it may have the potential to modulate P-gp-mediated drug efflux in humans. The aim of this study was to evaluate the effect of PIP on the pharmacokinetics of fexofenadine (FEX), a P-gp substrate, in healthy volunteers.

Methods

An open-label, two-period, sequential study involving 12 healthy volunteers was conducted. A single oral dose of FEX 120 mg was given to volunteers during the control phase and after the treatment phase. A once-daily oral dose of PIP 20 mg was given to volunteers during the treatment phase (10 days). Blood samples were collected at predefined time intervals, and plasma samples containing FEX were analyzed by liquid chromatography-tandem mass spectrometry.

Results

Treatment with PIP significantly increased maximum plasma concentration of FEX [406.9 (control) vs. 767 ng/mL (treatment)] and area under the plasma concentration–time curve [3403.7 (control) vs. 5724.7 ng.h/mL (treatment)] when compared to the control phase. In contrast, PIP treatment significantly decreased apparent oral clearance of FEX [35.4 (control) vs. 20.7 L/h (treatment)] as compared to the control. There was no significant change observed in the half life and renal clearance of FEX between the treatment phase and control phase.

Conclusions

The results suggest that altered pharmacokinetics and enhanced bioavailability of FEX might be attributed to PIP-mediated inhibition of P-gp drug efflux. Therefore, intake of PIP or dietary supplements containing PIP may potentially enhance the absorption or bioavailability of P-gp substrate drugs in addition to FEX.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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. Wilkinson GR (1997) The effects of diet, aging and disease-states on presystemic elimination and oral drug bioavailability in humans. Adv Drug Deliv Rev 27:129–159

    Article  CAS  PubMed  Google Scholar 

  2. Evans AM (2000) Influence of dietary components on the gastrointestinal metabolism and transport of drugs. Ther Drug Monit 22:131–136

    Article  CAS  PubMed  Google Scholar 

  3. Srinivasan K (2007) Black pepper and its pungent principle-piperine: a review of diverse physiological effects. Crit Rev Food Sci Nutr 47:735–748

    Article  CAS  PubMed  Google Scholar 

  4. Meghwal M, Goswami TK (2013) Piper nigrum and piperine: an update. Phytother Res 27:1121–1130

    Article  CAS  PubMed  Google Scholar 

  5. Bano G, Amla V, Raina RK, Zutshi U, Chopra CL (1987) The effect of piperine on pharmacokinetics of phenytoin in healthy volunteers. Planta Med 53:568–569

    Article  CAS  PubMed  Google Scholar 

  6. Velpandian T, Jasuja R, Bhardwaj RK, Jaiswal J, Gupta SK (2001) Piperine in food: interference in the pharmacokinetics of phenytoin. Eur J Drug Metab Pharmacokinet 26:241–247

    Article  CAS  PubMed  Google Scholar 

  7. Pattanaik S, Hota D, Prabhakar S, Kharbanda P, Pandhi P (2006) Effect of piperine on the steady-state pharmacokinetics of phenytoin in patients with epilepsy. Phytother Res 20:683–686

    Article  CAS  PubMed  Google Scholar 

  8. Pattanaik S, Hota D, Prabhakar S, Kharbanda P, Pandhi P (2009) Pharmacokinetic interaction of single dose of piperine with steady-state carbamazepine in epilepsy patients. Phytother Res 23:1281–1286

    Article  CAS  PubMed  Google Scholar 

  9. Rezaee MM, Kazemi S, Kazemi MT, Gharooee S, Yazdani E, Gharooee H et al (2014) The effect of piperine on midazolam plasma concentration in healthy volunteers, a research on the CYP3A-involving metabolism. Daru 22:8

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bano G, Raina RK, Zutshi U, Bedi KL, Johri RK, Sharma SC (1991) Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers. Eur J Clin Pharmacol 41:615–617

    Article  CAS  PubMed  Google Scholar 

  11. Han Y, Chin Tan TM, Lim LY (2008) In vitro and in vivo evaluation of the effects of piperine on P-gp function and expression. Toxicol Appl Pharmacol 230:283–289

    Article  CAS  PubMed  Google Scholar 

  12. Han HK (2011) The effects of black pepper on the intestinal absorption and hepatic metabolism of drugs. Expert Opin Drug Metab Toxicol 7:721–729

    Article  CAS  PubMed  Google Scholar 

  13. Koul S, Koul JL, Taneja SC, Dhar KL, Jamwal DS, Singh K et al (2000) Structure-activity relationship of piperine and its synthetic analogues for their inhibitory potentials of rat hepatic microsomal constitutive and inducible cytochrome P450 activities. Bioorg Med Chem 8:251–268

    Article  CAS  PubMed  Google Scholar 

  14. Atal CK, Dubey RK, Singh J (1985) Biochemical basis of enhanced drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism. J Pharmacol Exp Ther 232:258–262

    CAS  PubMed  Google Scholar 

  15. Volak LP, Ghirmai S, Cashman JR, Court MH (2008) Curcuminoids inhibit multiple human cytochromes P450, UDP-glucuronosyltransferase, and sulfotransferase enzymes, whereas piperine is a relatively selective CYP3A4 inhibitor. Drug Metab Dispos 36:1594–1605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF (2002) Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. J Pharmacol Exp Ther 302:645–650

    Article  CAS  PubMed  Google Scholar 

  17. Alhumayyd MS, Bukhari IA, Almotrefi AA (2014) Effect of piperine, a major component of black pepper, on the pharmacokinetics of domperidone in rats. J Physiol Pharmacol 65:785–789

    CAS  PubMed  Google Scholar 

  18. Jin MJ, Han HK (2010) Effect of piperine, a major component of black pepper, on the intestinal absorption of fexofenadine and its implication on food–drug interaction. J Food Sci 75:H93–H96

    Article  CAS  PubMed  Google Scholar 

  19. Simpson K, Jarvis B (2000) Fexofenadine: a review of its use in the management of seasonal allergic rhinitis and chronic idiopathic urticaria. Drugs 59:301–321

    Article  CAS  PubMed  Google Scholar 

  20. Kim KA, Park PW, Park JY (2009) Short-term effect of quercetin on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein, in healthy volunteers. Eur J Clin Pharmacol 65:609–614

    Article  CAS  PubMed  Google Scholar 

  21. Drescher S, Schaeffeler E, Hitzl M, Hofmann U, Schwab M, Brinkmann U (2002) MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine. Br J Clin Pharmacol 53:526–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB (1999) OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos 27:866–871

    CAS  PubMed  Google Scholar 

  23. Niemi M, Kivisto KT, Hofmann U, Schwab M, Eichelbaum M, Fromm MF (2005) Fexofenadine pharmacokinetics are associated with a polymorphism of the SLCO1B1 gene (encoding OATP1B1). Br J Clin Pharmacol 59:602–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shimizu M, Fuse K, Okudaira K, Nishigaki R, Maeda K, Kusuhara H et al (2005) Contribution of OATP (organic anion-transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans. Drug Metab Dispos 33:1477–1481

    Article  CAS  PubMed  Google Scholar 

  25. Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I (2004) Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human. J Pharmacol Exp Ther 308:438–445

    Article  PubMed  Google Scholar 

  26. Yasui-Furukori N, Uno T, Sugawara K, Tateishi T (2005) Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics. Clin Pharmacol Ther 77:17–23

    Article  CAS  PubMed  Google Scholar 

  27. Shimizu M, Uno T, Sugawara K, Tateishi T (2006) Effects of itraconazole and diltiazem on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein. Br J Clin Pharmacol 61:538–544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. van Heeswijk RP, Bourbeau M, Campbell P, Seguin I, Chauhan BM, Foster BC et al (2006) Time-dependent interaction between lopinavir/ritonavir and fexofenadine. J Clin Pharmacol 46:758–767

    Article  PubMed  Google Scholar 

  29. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 39:361–398

    Article  CAS  PubMed  Google Scholar 

  30. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1987) Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 84:7735–7738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fromm MF (2000) P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther 38:69–74

    Article  CAS  PubMed  Google Scholar 

  32. Bedada SK, Yakkanti SA, Neerati P (2014) Resveratrol enhances the bioavailability of fexofenadine in healthy human male volunteers: involvement of P-glycoprotein inhibition. J Bioequiv Availab 6:158–163

    Article  CAS  Google Scholar 

  33. Guo D, Zou J, Zhu Y, Lou S, Fan H, Qin Q (2010) Measurement of fexofenadine concentration in micro-sample human plasma by a rapid and sensitive LC-MS/MS employing protein precipitation: application to a clinical pharmacokinetic study. Biomed Chromatogr 24:335–341

    Article  CAS  PubMed  Google Scholar 

  34. Perloff MD, von Moltke LL, Greenblatt DJ (2002) Fexofenadine transport in Caco-2 cells: inhibition with verapamil and ritonavir. J Clin Pharmacol 42:1269–1274

    Article  CAS  PubMed  Google Scholar 

  35. Petri N, Tannergren C, Rungstad D, Lennernäs H (2004) Transport characteristics of fexofenadine in the Caco-2 cell model. Pharm Res 21:1398–1404

    Article  CAS  PubMed  Google Scholar 

  36. Khajuria A, Thusu N, Zutshi U (2002) Piperine modulates permeability characteristics of intestine by inducing alterations in membrane dynamics: influence on brush border membrane fluidity, ultrastructure and enzyme kinetics. Phytomedicine 9:224–231

    Article  CAS  PubMed  Google Scholar 

  37. Khajuria A, Zutshi U, Bedi KL (1998) Permeability characteristics of piperine on oral absorption—an active alkaloid from peppers and a bioavailability enhancer. Indian J Exp Biol 36:46–50

    CAS  PubMed  Google Scholar 

  38. Akamine Y, Miura M, Komori H, Saito S, Kusuhara H, Tamai I et al (2014) Effects of one-time apple juice ingestion on the pharmacokinetics of fexofenadine enantiomers. Eur J Clin Pharmacol 70:1087–1095

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Satish Kumar Bedada acknowledges the University Grants Commission (UGC), New Delhi, India for financial support to carry out this research work.

Author information

Authors and Affiliations

  1. Drug Metabolism and Pharmacokinetics Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, 506009, Telangana State, India

    Satish Kumar Bedada & Praveen Kumar Boga

Authors
  1. Satish Kumar Bedada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Praveen Kumar Boga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Satish Kumar Bedada.

Ethics declarations

The protocol was approved by an institutional human ethical committee and was conducted in compliance with the ethical principles from the Declaration of Helsinki and with all International Conference on Harmonisation Good Clinical Practice Guidelines. Informed consent was obtained from all the volunteers included in the study.

Conflict of interest

The authors declare that there are no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bedada, S.K., Boga, P.K. The influence of piperine on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy volunteers. Eur J Clin Pharmacol 73, 343–349 (2017). https://doi.org/10.1007/s00228-016-2173-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-016-2173-3

Keywords

Search

Navigation