Biomaterial Database

Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam. 1999

R Yuan, and D A Flockhart, and J D Balian

Office of Clinical Pharmacology and Biopharmaceutics, U.S. Food and Drug Administration (USFDA), Rockville, Maryland 20857, USA.

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.

UI	MeSH Term	Description	Entries
D007654	Ketoconazole	Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients.	Nizoral,R-41400,R41,400,R41400,R 41400
D008874	Midazolam	A short-acting hypnotic-sedative drug with anxiolytic and amnestic properties. It is used in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. The short duration and cardiorespiratory stability makes it useful in poor-risk, elderly, and cardiac patients. It is water-soluble at pH less than 4 and lipid-soluble at physiological pH.	Dormicum,Midazolam Hydrochloride,Midazolam Maleate,Ro 21-3981,Versed,Hydrochloride, Midazolam,Maleate, Midazolam,Ro 21 3981,Ro 213981
D003625	Data Collection	Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data.	Data Collection Methods,Dual Data Collection,Collection Method, Data,Collection Methods, Data,Collection, Data,Collection, Dual Data,Data Collection Method,Method, Data Collection,Methods, Data Collection
D004347	Drug Interactions	The action of a drug that may affect the activity, metabolism, or toxicity of another drug.	Drug Interaction,Interaction, Drug,Interactions, Drug
D004790	Enzyme Induction	An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis.	Induction, Enzyme
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000525	Alprazolam	A triazolobenzodiazepine compound with antianxiety and sedative-hypnotic actions, that is efficacious in the treatment of PANIC DISORDERS, with or without AGORAPHOBIA, and in generalized ANXIETY DISORDERS. (From AMA Drug Evaluations Annual, 1994, p238)	Alprazolan,Alprox,Apo-Alpraz,Cassadan,D-65MT,Esparon,Kalma,Novo-Alprazol,Nu-Alpraz,Ralozam,Tafil,Trankimazin,U-31,889,Xanax,Apo Alpraz,D65MT,Novo Alprazol,Nu Alpraz,U31,889
D014151	Anti-Anxiety Agents	Agents that alleviate ANXIETY, tension, and ANXIETY DISORDERS, promote sedation, and have a calming effect without affecting clarity of consciousness or neurologic conditions. ADRENERGIC BETA-ANTAGONISTS are commonly used in the symptomatic treatment of anxiety but are not included here.	Anti-Anxiety Agent,Anti-Anxiety Drug,Anxiolytic,Anxiolytic Agent,Anxiolytic Agents,Tranquilizing Agents, Minor,Anti-Anxiety Drugs,Anti-Anxiety Effect,Anti-Anxiety Effects,Antianxiety Effect,Antianxiety Effects,Anxiolytic Effect,Anxiolytic Effects,Anxiolytics,Tranquillizing Agents, Minor,Agent, Anti-Anxiety,Agent, Anxiolytic,Agents, Anti-Anxiety,Agents, Anxiolytic,Agents, Minor Tranquilizing,Agents, Minor Tranquillizing,Anti Anxiety Agent,Anti Anxiety Agents,Anti Anxiety Drug,Anti Anxiety Drugs,Anti Anxiety Effect,Anti Anxiety Effects,Drug, Anti-Anxiety,Drugs, Anti-Anxiety,Effect, Anti-Anxiety,Effect, Antianxiety,Effect, Anxiolytic,Effects, Anti-Anxiety,Effects, Antianxiety,Effects, Anxiolytic,Minor Tranquilizing Agents,Minor Tranquillizing Agents
D014229	Triazolam	A short-acting benzodiazepine used in the treatment of insomnia. Some countries temporarily withdrew triazolam from the market because of concerns about adverse reactions, mostly psychological, associated with higher dose ranges. Its use at lower doses with appropriate care and labeling has been reaffirmed by the FDA and most other countries.	Apo-Triazo,Gen-Triazolam,Halcion,Trilam,U-33,030,Apo Triazo,Gen Triazolam,U 33,030,U33,030