Piperine in food: interference in the pharmacokinetics of phenytoin

Eur J Drug Metab Pharmacokinet. Oct-Dec 2001;26(4):241-7. doi: 10.1007/BF03226378.


This study was carried out to explore the effect of piperine-containing food in altering the pharmacokinetics of phenytoin, an anti-epileptic drug with a narrow therapeutic index. A preliminary pharmacokinetic study was carried out in mice by administering phenytoin (10 mg) orally, with or without piperine (0.6 mg). Subsequently, oral pharmacokinetics of phenytoin was carried out in six healthy volunteers in a crossover design. Phenytoin tablet (300 mg) was given 30 minutes after ingestion of a soup (melahu rasam) with or without black pepper. A further study of intavenous pharmacokinetics of phenytoin (1 mg) in rats with or without oral pretreatment with piperine (10 mg) was also conducted. The phenytoin concentration in the serum was analyzed by HPLC. The study showed a significant increase in the kinetic estimates of Ka, AUC(0-10) and AUC(0-infinity) in the piperine-fed mice. Similarly, in human volunteers piperine increased Ka, AUC(0-48), AUC(0-infinity), and delayed elimination of phenytoin. Intravenous phenytoin in the oral piperine-treated rat group showed a significant alteration in the elimination phase indicating its metabolic blockade. The significance of this finding in epileptic patients maintained on phenytoin therapy requires further investigation. This study may also have implications in the case of other drugs having a low therapeutic index.

MeSH terms

  • Administration, Oral
  • Adult
  • Alkaloids*
  • Animals
  • Anticonvulsants / administration & dosage
  • Anticonvulsants / pharmacokinetics*
  • Benzodioxoles
  • Chromatography, High Pressure Liquid
  • Female
  • Food Analysis
  • Humans
  • Male
  • Mice
  • Phenytoin / administration & dosage
  • Phenytoin / pharmacokinetics*
  • Piper nigrum / adverse effects*
  • Piper nigrum / chemistry
  • Piperidines / analysis*
  • Polyunsaturated Alkamides
  • Rats
  • Rats, Wistar


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