Effect of piperine on the steady-state pharmacokinetics of phenytoin in patients with epilepsy

Phytother Res. 2006 Aug;20(8):683-6. doi: 10.1002/ptr.1937.


Piperine, the active principle of Piper longum, Piper nigrum and Zingiber officinalis, has been reported to enhance the oral bioavailability of phenytoin in human volunteers. The objective of this study was to explore the effect of a single dose of piperine in patients with uncontrolled epilepsy on the steady-state pharmacokinetics of phenytoin. Two groups of 10 patients each receiving either a 150 mg or 200 mg twice daily dose of phenytoin were selected. Twelve hours after the night dose, venous blood samples were collected at 0, 0.5, 1, 2, 4, 6, 9, 12 h after administration of phenytoin. On the next study day, piperine 20 mg was administered along with phenytoin and samples were collected similarly. The mean plasma drug concentrations at different time points and the pharmacokinetic parameters before and after piperine administration were compared by Student's t-test. Piperine increased significantly the mean plasma concentration of phenytoin at most of the time points in both dose groups. There was a significant increase in AUC((0-12h)) (p < 0.01), C(max) (p < 0.001) and K(a) (p < 0.05) whereas the changes in K(el) and t(max) were not significant. The results showed that piperine enhanced the bioavailability of phenytoin significantly, possibly by increasing the absorption.

MeSH terms

  • Adult
  • Alkaloids / adverse effects*
  • Anticonvulsants / pharmacokinetics*
  • Anticonvulsants / therapeutic use
  • Area Under Curve
  • Benzodioxoles
  • Biological Availability
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Epilepsy / drug therapy
  • Epilepsy / metabolism*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Phenytoin / pharmacokinetics*
  • Phenytoin / therapeutic use
  • Piper*
  • Piperidines / adverse effects*
  • Polyunsaturated Alkamides


  • Alkaloids
  • Anticonvulsants
  • Benzodioxoles
  • Piperidines
  • Polyunsaturated Alkamides
  • Phenytoin
  • piperine