title: Diltiazem enhances the effects of triazolam by inhibiting its metabolism.
abstract: BACKGROUND
  Triazolam is metabolized by CYP3A4. Diltiazem is an inhibitor of this isozyme and interacts with midazolam, another substrate of this enzyme. Therefore the possible interaction between triazolam and diltiazem is worth investigation.
  
  
  METHODS
  A balanced, randomized, double-blind crossover study design was used, with an interval of 2 weeks between phases. Ten healthy volunteers were given 60 mg diltiazem orally or placebo three times a day for 2 days. On the second day they received a single 0.25 mg oral dose of triazolam, after which plasma samples were collected and effects of triazolam measured for up to 17 hours.
  
  
  RESULTS
  Diltiazem increased the mean area under the triazolam concentration-time curve threefold (p < 0.001) and the elimination half-life (p < 0.001) and the peak plasma concentration of triazolam twofold (p < 0.005). The increased concentrations of triazolam during the diltiazem phase were associated with increased and prolonged pharmacodynamic effects.
  
  
  CONCLUSIONS
  Diltiazem has a clinically significant interaction with oral triazolam. The data is highly suggestive that diltiazem inhibits the metabolism of triazolam during the first-pass and elimination phases. Prescription of triazolam should be avoided if a patient is using diltiazem or other potent inhibitors of CYP3A.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Varhe
authors.forename: K T
authors.initials: KT
authors.lastname: Olkkola
authors.forename: P J
authors.initials: PJ
authors.lastname: Neuvonen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002317:Cardiovascular Agents / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004110:Diltiazem / Q000494:pharmacology*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics*; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D012016:Reference Values; D014229:Triazolam / Q000493:pharmacokinetics*
chemical_list: D002317:Cardiovascular Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D014229:Triazolam; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004110:Diltiazem