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

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

Research output: Contribution to journalArticle

73 Citations (Scopus)

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, C(max), t(1/2), and t(max) 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 iris 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. (C) 1999 the American College of Clinical Pharmacology.

Original languageEnglish (US)
Pages (from-to)1109-1125
Number of pages17
JournalJournal of Clinical Pharmacology
Volume39
Issue number11
StatePublished - 1999
Externally publishedYes

Fingerprint

Triazolam
Alprazolam
Midazolam
Benzodiazepines
Drug Interactions
Pharmacokinetics
Ketoconazole
Itraconazole
Carbamazepine
Phenytoin
Iris
Rifampin
Pharmaceutical Preparations
Patient Selection
Area Under Curve
Databases
Prospective Studies

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam. / Yuan, R.; Flockhart, D. A.; Balian, J. D.

In: Journal of Clinical Pharmacology, Vol. 39, No. 11, 1999, p. 1109-1125.

Research output: Contribution to journalArticle

@article{9ef0f323628f4ba6899e03002cddf8b6,
title = "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, C(max), t(1/2), and t(max) 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 iris 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. (C) 1999 the American College of Clinical Pharmacology.",
author = "R. Yuan and Flockhart, {D. A.} and Balian, {J. D.}",
year = "1999",
language = "English (US)",
volume = "39",
pages = "1109--1125",
journal = "Journal of Clinical Pharmacology",
issn = "0091-2700",
publisher = "SAGE Publications Inc.",
number = "11",

}

TY - JOUR

T1 - Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam

AU - Yuan, R.

AU - Flockhart, D. A.

AU - Balian, J. D.

PY - 1999

Y1 - 1999

N2 - 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, C(max), t(1/2), and t(max) 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 iris 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. (C) 1999 the American College of Clinical Pharmacology.

AB - 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, C(max), t(1/2), and t(max) 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 iris 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. (C) 1999 the American College of Clinical Pharmacology.

UR - http://www.scopus.com/inward/record.url?scp=0033323791&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033323791&partnerID=8YFLogxK

M3 - Article

C2 - 10579141

AN - SCOPUS:0033323791

VL - 39

SP - 1109

EP - 1125

JO - Journal of Clinical Pharmacology

JF - Journal of Clinical Pharmacology

SN - 0091-2700

IS - 11

ER -