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

This review was conducted to identify the current data on drug interactions with alprazolam, midazolam, and triazolam to guide practitioners in the us e of these drugs. The Medline electronic database from 1966 through 1998 wa s used to identify clinical studies of the pharmacokinetic effect of drugs on these three benzodiazepines. Of a total of 491 literature reports identi fied, 59 prospective studies met our selection criteria. The pharmacokineti c parameters of AUC, C-max, t(1/2), and t(max) were evaluated for changes f ollowing an interaction. To allow comparison between studies, changes in th e parameters were normalized relative to the control values. Pharmacodynami c effects and measures, when reported in the original studies as statistica lly significant, were classified as a strong interaction, and when the inte raction was present but not statistically significant, they were classified as mild in this review. As a result, clinically significant drug interacti ons were noted for all three benzodiazepines, although it is clear that sta tistically significant pharmacokinetic changes do not always translate into clinically significant pharmacodynamic consequences. All three benzodiazep ines were susceptible to drug interactions, but oral dosing of midazolam an d triazolam resulted in greater alterations in the pharamcokinetic paramete rs than alprazolam due to their larger presystemic extraction. Ketoconazole and itraconazole were found to be the most potent metabolic inhibitors tha t prolonged the duration of or intensified the magnitude of the dynamic res ponse produced by the three benzodiazepines. Rifampin, carbamazepine, and p henytoin were noted to be potent metabolic inducers, and their treatments r esult in loss of benzodiazepine therapeutic efficacy In conclusion, potent metabolic inhibitors and inducers can either significantly prolong or dimin ish the dynamic effects of benzodiazepines via their influence on the pharm acokinetics of benzodiazepines. (C)1999 the American College of Clinical Ph armacology.