Mibefradil but not isradipine substantially elevates the plasma concentrations of the CYP3A4 substrate triazolam.
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 However, their in vivo inhibitory effects on CYP3A4 are not known in detail, although mibefradil was recently withdrawn from the market because of serious drug interactions.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.


CONCLUSIONS
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.
Backman
J T
JT
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland. janne.backman@huch.fi
Wang
J S
JS
Wen
X
X
Kivistö
K T
KT
Neuvonen
P J
PJ
D000284:Administration, Oral; D000328:Adult; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; 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 / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D017275:Isradipine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D020748:Mibefradil / Q000008:administration & dosage / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000097:blood; D014229:Triazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D014151:Anti-Anxiety Agents; D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D014229:Triazolam; D020748:Mibefradil; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017275:Isradipine