Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam

Abstract

This review was conducted to identify the current data on drug interactions with alprazolam, midazolam, and triazolam to guide practitioners in the use of these drugs. The Medline electronic database from 1966 through 1998 was used to identify clinical studies of the pharmacokinetic effect of drugs on these three benzodiazepines. Of a total of 491 literature reports identified, 59 prospective studies met our selection criteria. The pharmacokinetic parameters of AUC, Cmax, t1/2, and tmax were evaluated for changes following an interaction. To allow comparison between studies, changes in the parameters were normalized relative to the control values. Pharmacodynamic effects and measures, when reported in the original studies as statistically significant, were classified as a strong interaction, and when the interaction was present but not statistically significant, they were classified as mild in this review. As a result, clinically significant drug interactions were noted for all three benzodiazepines, although it is clear that statistically significant pharmacokinetic changes do not always translate into clinically significant pharmacodynamic consequences. All three benzodiazepines were susceptible to drug interactions, but oral dosing of midazolam and triazolam resulted in greater alterations in the pharmacokinetic parameters than alprazolam due to their larger presystemic extraction. Ketoconazole and itraconazole were found to be the most potent metabolic inhibitors that prolonged the duration of or intensified the magnitude of the dynamic response produced by the three benzodiazepines. Rifampin, carbamazepine, and phenytoin were noted to be potent metabolic inducers, and their treatments result in loss of benzodiazepine therapeutic efficacy. In conclusion, potent metabolic inhibitors and inducers can either significantly prolong or diminish the dynamic effects of benzodiazepines via their influence on the pharmacokinetics of benzodiazepines.