Effect of piperine on CYP2E1 enzyme activity of chlorzoxazone in healthy volunteers

Xenobiotica. 2017 Dec;47(12):1035-1041. doi: 10.1080/00498254.2016.1241450. Epub 2016 Nov 16.


1. The purpose of the present study was to investigate the effect of piperine (PIP) on CYP2E1 enzyme activity and pharmacokinetics of chlorzoxazone (CHZ) in healthy volunteers. 2. An open-label, two period, sequential study was conducted in 12 healthy volunteers. A single dose of PIP 20 mg was administered daily for 10 days during treatment phase. A single dose of CHZ 250 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected at predetermined time intervals after CHZ dosing and analyzed by HPLC. 3. Treatment with PIP significantly enhanced maximum plasma concentration (Cmax) (3.14-4.96 μg/mL), area under the curve (AUC) (10.46-17.78 μg h/mL), half life (T1/2) (1.26-1.82 h) and significantly decreased elimination rate constant (Kel) (0.57-0.41 h - 1), apparent oral clearance (CL/F) (24.76-13.65 L/h) of CHZ when compared to control. In addition, treatment with PIP significantly decreased Cmax (0.22-0.15 μg/mL), AUC (0.94-0.68 μg h/mL), T1/2 (2.54-1.68 h) and significantly increased Kel (0.32-0.43 h - 1) of 6-hydroxychlorzoxazone (6-OHCHZ) as compared to control. Furthermore, treatment with PIP significantly decreased metabolite to parent (6-OHCHZ/CHZ) ratios of Cmax, AUC, T1/2 and significantly increased Kel ratio of 6-OHCHZ/CHZ, which indicate the decreased formation of CHZ to 6-OHCHZ. 4. The results suggest that altered pharmacokinetics of CHZ might be attributed to PIP mediated inhibition of CYP2E1 enzyme, which indicate significant pharmacokinetic interaction present between PIP and CHZ. The inhibition of CYP2E1 by PIP may represent a novel therapeutic benefit for minimizing ethanol induced CYP2E1 enzyme activity and results in reduced hepatotoxicity of ethanol.

Keywords: CYP2E1 enzyme; Chlorzoxazone; hepatotoxicity; metabolism; pharmacokinetics; piperine.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Alkaloids / metabolism
  • Alkaloids / pharmacology*
  • Area Under Curve
  • Benzodioxoles / metabolism
  • Benzodioxoles / pharmacology*
  • Chlorzoxazone / metabolism
  • Chlorzoxazone / pharmacology*
  • Cytochrome P-450 CYP2E1 / metabolism*
  • Cytochrome P-450 Enzyme Inhibitors / metabolism
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology*
  • Drug Interactions*
  • Female
  • Half-Life
  • Humans
  • Male
  • Muscle Relaxants, Central / metabolism
  • Muscle Relaxants, Central / pharmacology*
  • Piperidines / metabolism
  • Piperidines / pharmacology*
  • Polyunsaturated Alkamides / metabolism
  • Polyunsaturated Alkamides / pharmacology*


  • Alkaloids
  • Benzodioxoles
  • Cytochrome P-450 Enzyme Inhibitors
  • Muscle Relaxants, Central
  • Piperidines
  • Polyunsaturated Alkamides
  • Cytochrome P-450 CYP2E1
  • Chlorzoxazone
  • piperine