Pharmacokinetics of midazolam given as an intranasal spray to adult surgical patients

Abstract

The aim of this study was to determine the bioavailability and absorption kinetics of midazolam given as an intranasal (i.n.) spray. In addition, plasma concentrations of the active metabolite, 1-hydroxymidazolam, were measured to give an indication of enteral absorption. An i.v. and i.n. midazolam dose were given in a crossover study to 14 adult surgical patients. Individual uptake profiles of i.n. midazolam were estimated by numerical deconvolution. After an i.n. dose of 0.15 mg kg-1, maximum arterial plasma concentrations were 192 (SD 48) micrograms litre-1 at 14 (2) min. Uptake of midazolam was rapid and bioavailability was 83 (15)%. Formation of the 1-hydroxy metabolite after i.n. administration did not exceed that after the i.v. dose. This demonstrates that under optimal conditions absorption of midazolam via the nasal mucosa was virtually complete. In this case little midazolam was swallowed and subjected to first-pass metabolism in the liver and therefore pharmacologically important amounts of active metabolite were not produced. Routinely administering i.n. midazolam under the assumption that the bioavailability is approximately 50% (as reported previously in the literature) may lead to overdosing in some patients.