Study on influence of piperine treatment on the pharmacokinetics of diclofenac in healthy volunteers

Xenobiotica. 2017 Feb;47(2):127-132. doi: 10.3109/00498254.2016.1163752. Epub 2016 Apr 6.


1. Diclofenac sodium (DIC) is a widely used anti-inflammatory drug and its administration in humans receiving long-term therapy with herbal drugs containing piperine (PIP) may occur, which leads to drug-phytochemical interactions. The purpose of the present study was to investigate the influence of PIP treatment on the pharmacokinetics of DIC in healthy volunteers. 2. The open-label, two period, sequential study was conducted in 12 healthy volunteers. PIP 20 mg was administered once daily for 10 days during treatment phase. A single dose of DIC 100 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected after DIC dosing at predetermined time intervals and analyzed by HPLC. 3. Treatment with PIP significantly enhanced maximum plasma concentration (Cmax) (2.24-3.68 μg/mL, p < 0.05), area under the curve (AUC) (7.09-11.81 μg h/mL, p < 0.05), half-life (T1/2) (1.23-1.65 h, p < 0.05) and significantly decreased elimination rate constant (Kel) (0.62-0.41 h-1, p < 0.05), apparent oral clearance (CL/F) (7.57-4.52 L/h, p < 0.05) of DIC as compared to that of control phase. 4. The results suggest that the altered pharmacokinetics of DIC might be attributed to PIP mediated inhibition of CYP2C9 enzyme, which indicates the clinically significant interaction present between DIC and PIP. Therefore, the combination therapy of DIC along with PIP may represent a novel approach to reduce dosage and result in reduced incidence of gastrointestinal side effects seen with DIC alone at higher doses.

Keywords: Bioavailability; CYP2C9 enzyme; diclofenac; metabolism; pharmacokinetics; piperine.

MeSH terms

  • Adult
  • Alkaloids / adverse effects
  • Alkaloids / therapeutic use*
  • Area Under Curve
  • Benzodioxoles / adverse effects
  • Benzodioxoles / therapeutic use*
  • Cytochrome P-450 Enzyme Inhibitors / adverse effects
  • Cytochrome P-450 Enzyme Inhibitors / therapeutic use*
  • Diclofenac / pharmacokinetics*
  • Drug Interactions
  • Female
  • Half-Life
  • Healthy Volunteers
  • Humans
  • Male
  • Piperidines / adverse effects
  • Piperidines / therapeutic use*
  • Polyunsaturated Alkamides / adverse effects
  • Polyunsaturated Alkamides / therapeutic use*


  • Alkaloids
  • Benzodioxoles
  • Cytochrome P-450 Enzyme Inhibitors
  • Piperidines
  • Polyunsaturated Alkamides
  • Diclofenac
  • piperine