Background: Triazolam is metabolized predominantly by cytochrome P450 3A4 (CYP3A4). Rifampin (rifampicin) is a potent inducer of CYP3A4 and it is known to markedly reduce plasma concentrations and effects of drugs such as midazolam. The possible interaction between rifampin and triazolam was examined in this study.
Methods: The pharmacokinetics and pharmacodynamics of triazolam were investigated in a randomized, double-blind crossover study with two phases. Ten young healthy volunteers took either 600 mg rifampin once daily or placebo for 5 days. On the sixth day, 0.5 mg triazolam was administered orally. Timed blood samples were collected and the effects of triazolam were measured with five psychomotor tests for 10 hours.
Results: The area under the plasma triazolam concentration-time curve in the rifampin phase was only 5.1% of that in the placebo phase (0.74 +/- 0.14 versus 14.8 +/- 1.0 ng.hr/ml [mean +/- SEM; p < 0.001]). Rifampin pretreatment decreased the maximum plasma concentration of triazolam to 12.4% of the control value (i.e., from 2.9 +/- 0.2 to 0.36 +/- 0.06 ng/ml [p < 0.001]) and the elimination half-life from 2.8 +/- 0.1 to 1.3 +/- 0.1 hours (p < 0.001). All psychomotor tests showed markedly reduced effects (p < 0.01) of triazolam after rifampin pretreatment.
Conclusions: Triazolam is ineffective during rifampin treatment. This is most likely due to increased metabolism of triazolam after induction of CYP3A4 in the gut wall and liver by rifampin. It is advisable to use hypnotic agents that are not metabolized by CYP3A4 during treatment with rifampin or other potent inducers of CYP3A4.