Mechanism for the interaction between triazolam and cimetidine

Area of Science:

• Pharmacokinetics
• Drug Metabolism
• Gastrointestinal Physiology

Background:

• Triazolam is a benzodiazepine used for insomnia.
• Understanding its absorption and drug interactions is crucial for safe and effective use.
• Intraduodenal administration allows for study of presystemic hydrolysis and absorption.

Purpose of the Study:

• To investigate the impact of intraduodenal pH on triazolam absorption and presystemic hydrolysis.
• To evaluate the effect of cimetidine on triazolam pharmacokinetics.
• To elucidate the mechanism of the triazolam-cimetidine interaction.

Main Methods:

• Four healthy volunteers received intraduodenal infusions of triazolam at pH 2.3 and pH 6.0.
• A third treatment involved pH 6.0 triazolam with concurrent cimetidine administration.
• Pharmacokinetic parameters, including AUC and Cmax, were measured.

Main Results:

• Hydrolysis of triazolam to triazolo-benzophenone (TB) occurred at pH 2.3 but not pH 6.0.
• TB was stable in serum, with minimal systemic absorption observed.
• No significant difference in triazolam pharmacokinetics was found between pH 2.3 and pH 6.0 treatments.
• Cimetidine increased triazolam AUC infinity by 54% and Cmax by 35%.

Conclusions:

• Triazolo-benzophenone undergoes extensive presystemic conversion to triazolam.
• The interaction between triazolam and cimetidine primarily involves reduced triazolam clearance.
• Intraduodenal pH does not significantly influence triazolam absorption in this study.