Effects of blood and brain midazolam concentrations on prolonged sedation in rats with low albumin levels.

Abstract

Midazolam is a short-acting benzodiazepine widely used for sedation; however, its duration of action can be prolonged by various factors including hypoalbuminemia. Previous behavioral studies in rats with low albumin levels reported reduced muscle strength and spontaneous locomotion, but the relationship between hypoalbuminemia and midazolam pharmacokinetics remains unclear. This study investigated whether prolonged midazolam sedation in hypoalbuminemia correlates with unbound and brain midazolam concentrations. Low-albumin rats were generated using protein-controlled diets for 30 days. Midazolam (5 mg/kg, i. p.) was administered and total blood and brain concentrations were determined by high-performance liquid chromatography 10 and 60 minutes after administration. Compared to controls, low albumin rats showed significantly higher total blood concentrations at 60 minutes (0.27 ± 0.02 vs 0.12 ± 0.02 μg/mL) and brain concentrations (0.21 ± 0.02 vs 0.10 ± 0.03 μg/mL). Unbound concentrations remained below quantification limits due to ultrafiltration adsorption. Pharmacokinetic analysis revealed prolonged half-life and decreased clearance in low-albumin rats. These findings suggest that hypoalbuminemia prolonged midazolam actions through sustained blood and brain concentrations, likely due to increased initial unbound drug levels that rapidly distribute to the brain before accumulating in peripheral tissues. Clinicians should exercise caution when administering midazolam to patients with hypoalbuminemia.