Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers

Clin Pharmacol Ther. 2002 Jan;71(1):46-56. doi: 10.1067/mcp.2002.121217.


Background: Modafinil has been reported to produce a concentration-related induction of CYP3A4/5 activity in vitro in primary cultures of human hepatocytes.

Objective: Our objective was to determine whether the pharmacokinetics of steady-state ethinyl estradiol (INN, ethinylestradiol) and single-dose triazolam were altered after 4 weeks of modafinil treatment in volunteers.

Methods: This was a placebo-controlled, single-blind, single-period study in 41 female subjects who were receiving long-term treatment with an oral contraceptive that contained ethinyl estradiol (0.035 mg) and norgestimate (0.180-0.250 mg). Pharmacokinetic profiles for ethinyl estradiol and for a single oral dose of triazolam (0.125 mg) were obtained the day before initiation of treatment with modafinil (200 mg for 7 days, followed by 400 mg for 21 days) or placebo (28 days). A second dose of triazolam was administered with the final dose of modafinil, and pharmacokinetic profiling was repeated.

Results: The modafinil treatment group had a marked decrease in maximum observed plasma concentrations and areas under the plasma concentration-time curve for triazolam relative to placebo, with a much smaller decrease in these parameters for ethinyl estradiol. The half-life of triazolam was also decreased, but the half-life of ethinyl estradiol did not appear to be affected by treatment with modafinil.

Conclusion: Modafinil induced CYP3A4/5 activity in humans in vivo, suggesting that there is potential for metabolic drug-drug interactions between modafinil and substrates of CYP3A4/5. However, the induction appeared to be more gastrointestinal than hepatic in nature. Therefore significant metabolic drug-drug interactions are most likely to occur with compounds (such as triazolam) that undergo significant gastrointestinal CYP3A4/5-mediated first-pass metabolism.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Area Under Curve
  • Benzhydryl Compounds / adverse effects
  • Benzhydryl Compounds / pharmacology*
  • Biomarkers
  • Central Nervous System Stimulants / adverse effects
  • Central Nervous System Stimulants / pharmacology*
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Interactions
  • Estradiol Congeners / adverse effects
  • Estradiol Congeners / pharmacokinetics*
  • Ethinyl Estradiol / adverse effects
  • Ethinyl Estradiol / pharmacokinetics*
  • Female
  • Gas Chromatography-Mass Spectrometry
  • Half-Life
  • Humans
  • Hypnotics and Sedatives / adverse effects
  • Hypnotics and Sedatives / pharmacokinetics*
  • Mass Spectrometry
  • Mixed Function Oxygenases / metabolism
  • Modafinil
  • Single-Blind Method
  • Spectrophotometry, Ultraviolet
  • Triazolam / adverse effects
  • Triazolam / pharmacokinetics*


  • Benzhydryl Compounds
  • Biomarkers
  • Central Nervous System Stimulants
  • Estradiol Congeners
  • Hypnotics and Sedatives
  • Triazolam
  • Ethinyl Estradiol
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Modafinil