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Oral single doses of erythromycin and roxithromycin may increase the effects of midazolam on human performance
M J Mattila1, J J Idänpään-Heikkilä, M Törnwall
1Department of Pharmacology and Toxicology, University of Helsinki, Finland.
Abstract:
Macrolide antibiotics are known to inhibit the metabolism of triazolam and midazolam in vitro and in vivo. To find out if significant interactions take place after single oral doses of these agents to man, 0.25 mg triazolam and 5, 10 and 15 mg of midazolam in capsule from were given with and without 750 mg erythromycin or 300 mg roxithromycin to parallel groups of healthy subjects in four placebo-controlled double-blind studies. Objective tests and subjective assessments were made before the intake of hypnotics and 30 and 90 min after it. In Study I, triazolam impaired letter cancellation, the combination triazolam+erythromycin impaired digit symbol substitution and letter cancellation, and triazolam+roxithromycin impaired digit symbol substitution, all at 90 min. In Study II, midazolam 5 mg and midazolam 10 mg proved quite inert but the combination midazolam 5 mg+erythromycin impaired digit symbol substitution. In Study III, both midazolam 10 mg and midazolam 15 mg impaired digit substitution and letter cancellation, the effects of 15 mg being more prominent. The strongest drug effects were found with midazolam 10 mg+erythromycin which differed from placebo and midazolam (10 mg and 15 mg) in several objective and subjective test variables. In Study IV, the combination midazolam 10 mg+roxithromycin impaired several objective and subjective variables but it was not stronger than midazolam 15 mg. These results were supported by the direct measurements of plasma midazolam in three subjects: erythromycin increased plasma midazolam more than roxithromycin and enhanced midazolam effects following the intake of midazolam 10 mg.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Macrolide antibiotics like erythromycin and roxithromycin can interact with triazolam and midazolam. Erythromycin significantly increased midazolam levels and effects, while roxithromycin had a lesser impact.
Area of Science:
- Pharmacology
- Drug Interactions
- Clinical Pharmacology
Background:
- Macrolide antibiotics are known inhibitors of cytochrome P450 enzymes, affecting drug metabolism.
- Triazolam and midazolam are commonly prescribed benzodiazepines metabolized by CYP3A4.
- Potential interactions between macrolides and these benzodiazepines warrant investigation in humans.
Purpose of the Study:
- To evaluate the pharmacokinetic and pharmacodynamic interactions between oral macrolide antibiotics (erythromycin, roxithromycin) and single doses of triazolam and midazolam in healthy subjects.
- To determine if these interactions lead to clinically significant adverse effects.
Main Methods:
- Four parallel-group, placebo-controlled, double-blind studies were conducted.
- Healthy subjects received single oral doses of triazolam (0.25 mg) or midazolam (5, 10, or 15 mg) alone or in combination with erythromycin (750 mg) or roxithromycin (300 mg).
- Cognitive function was assessed using objective tests and subjective measures at baseline and at 30 and 90 minutes post-ingestion.
Main Results:
- Erythromycin significantly potentiated the cognitive impairment caused by triazolam and midazolam, with the strongest effects observed with midazolam 10 mg + erythromycin.
- Roxithromycin also caused some impairment when combined with triazolam or midazolam, but the effects were generally less pronounced than with erythromycin.
- Plasma midazolam concentrations were higher when co-administered with erythromycin compared to roxithromycin, correlating with enhanced pharmacodynamic effects.
Conclusions:
- Erythromycin poses a significant risk of drug interactions with triazolam and midazolam, leading to enhanced central nervous system effects.
- Roxithromycin may also interact, but to a lesser extent than erythromycin.
- Caution is advised when prescribing macrolide antibiotics concurrently with triazolam or midazolam, particularly erythromycin.