Propofol increases the rate of albumin-unbound free midazolam in serum albumin solution

Propofol and midazolam have a synergistic anesthetic action. One of the reasons for this is thought to be the inhibitory effect of propofol on midazolam metabolism. However, because both drugs bind strongly to serum protein, their interaction may not only involve the effects of propofol on midazolam metabolism, but may also involve propofol’s effects on serum protein-binding. Against this background, we investigated the characteristics of midazolam binding to serum albumin, and evaluated the effects of both propofol and ketamine on this binding. Midazolam was added to a serum albumin solution with propofol or ketamine, and, after incubation for 1 h, albumin-free solution was separated from the sample and the midazolam concentration was measured using a high-performance liquid chromatography system. The albumin-unbound rate of midazolam was evaluated and compared with the rate in the control solution (only midazolam). Propofol significantly raised the rate of albumin-unbound free midazolam, while ketamine had no effect on the binding of midazolam to serum albumin. These findings suggest that the increase in albumin-unbound free midazolam brought about by propofol is involved in the synergistic effect of these two agents.