Enhanced effect of triazolam with diltiazem.
OBJECTIVE
Triazolam, a triazolobenzodiazepine hypnotic agent, is metabolized by CYP3A4. Diltiazem is an inhibitor of this isozyme. The aim of this study was to determine if diltiazem affects plasma concentrations of triazolam in humans.


METHODS
We investigated the interaction between triazolam and diltiazem in a randomized, three-phase crossover study. Seven healthy male volunteers received orally either a single 0.25 mg dose of triazolam, a 0.25 mg dose of triazolam after a 3-day treatment of diltiazem (180 mg day-1), or a placebo. Plasma samples were collected to determine triazolam concentration over a 24 h period. The pharmacodynamic effects of triazolam were investigated using the peak saccadic velocity of eye movements (PSV), electroencephalogram (EEG), and visual analogue scale (VAS) through 8 h.


RESULTS
Diltiazem pretreatment significantly increased the area under the triazolam concentration-time curve (8.0 +/- 2.4 to 18.2 +/- 3.1 ng ml-1 h; P < 0.001; mean +/- s.d.). Peak triazolam concentration was increased (2.1 +/- 0.7 to 3.6 +/- 1.0 ng ml-1, P < 0.05) and the elimination half-life prolonged (4.1 +/- 2.1 to 7.6 +/- 1.9 h; P < 0.01). The PSV, EEG, and VAS of the triazolam plus diltiazem group revealed significant differences from the triazolam alone group or the control placebo group.


CONCLUSIONS
Diltiazem markedly affects the pharmacokinetics of triazolam and increases the intensity of its sedative effects. Inhibition of CYP3A isozyme by diltiazem may explain the observed pharmacokinetic interaction. Therefore, triazolam should be avoided when patients are using diltiazem.
Kosuge
K
K
Department of Clinical Pharmacology, Hamamatsu University School of Medicine, Japan.
Nishimoto
M
M
Kimura
M
M
Umemura
K
K
Nakashima
M
M
Ohashi
K
K
D000284:Administration, Oral; D000328:Adult; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004110:Diltiazem / Q000008:administration & dosage / Q000494:pharmacology*; D004311:Double-Blind Method; D004357:Drug Synergism; D004569:Electroencephalography / Q000187:drug effects; D005133:Eye Movements / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D014229:Triazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D014229:Triazolam; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004110:Diltiazem