Mibefradil but not isradipine substantially elevates the plasma concentrations of the CYP3A4 substrate triazolam

Clin Pharmacol Ther. 1999 Oct;66(4):401-7. doi: 10.1053/cp.1999.v66.a101461.


Background: The calcium channel blockers mibefradil and isradipine inhibit CYP3A4 in vitro. However, their in vivo inhibitory effects on CYP3A4 are not known in detail, although mibefradil was recently withdrawn from the market because of serious drug interactions.

Methods: The effects of mibefradil and isradipine on the pharmacokinetics and pharmacodynamics of oral triazolam, a model substrate of CYP3A4, were studied in a randomized, double-blind crossover study with three phases. Nine healthy subjects took 50 mg mibefradil, 5 mg isradipine, or placebo orally once a day for 3 days. On day 3, each subject received a single 0.25 mg oral dose of triazolam. Thereafter, blood samples were collected up to 18 hours, and pharmacodynamic effects of triazolam were measured up to 8 hours.

Results: Mibefradil increased the total area under the plasma triazolam concentration-time curve [AUC(0 - infinity)] 9-fold compared with placebo (P < .001). The peak plasma concentration of triazolam was increased 1.8-fold (3.4+/-0.1 ng/mL versus 1.8+/-0.2 ng/mL [mean +/- SEM]; P < .001), and the elimination half-life (t 1/2) was increased 4.9-fold (18.5+/-1.9 hours versus 4.0+/-0.5 hours; P < .001) by mibefradil. In addition, mibefradil was associated with increased pharmacodynamic effects of triazolam. In contrast to mibefradil, isradipine reduced the AUC(0 - infinity) and t 1/2 of triazolam by about 20% (P < .05) and had no significant effects on the pharmacodynamics of triazolam.

Conclusion: Mibefradil but not isradipine markedly increases the plasma concentrations of triazolam and thereby enhances and prolongs its pharmacodynamic effects, consistent with potent inhibition of CYP3A4.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Anti-Anxiety Agents / administration & dosage
  • Anti-Anxiety Agents / blood
  • Anti-Anxiety Agents / pharmacokinetics*
  • Area Under Curve
  • Calcium Channel Blockers / administration & dosage
  • Calcium Channel Blockers / pharmacology*
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / blood
  • Double-Blind Method
  • Female
  • Humans
  • Isradipine / administration & dosage
  • Isradipine / pharmacology*
  • Male
  • Mibefradil / administration & dosage
  • Mibefradil / pharmacology*
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Mixed Function Oxygenases / blood
  • Triazolam / administration & dosage
  • Triazolam / blood
  • Triazolam / pharmacokinetics*


  • Anti-Anxiety Agents
  • Calcium Channel Blockers
  • Cytochrome P-450 Enzyme Inhibitors
  • Triazolam
  • Mibefradil
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Isradipine