Binding of propofol to blood components: implications for pharmacokinetics and for pharmacodynamics

AIMS: Propofol is a widely used i.v. anaesthetic agent. However, its binding properties to blood components have not been fully studied. METHODS: We studied the binding of propofol to erythrocytes, to human serum and to isolated serum proteins. Because propofol bound to ultrafiltration and equilibrium dialysis membranes, we used a co-binding technique with dextran coated charcoal and with erythrocytes. RESULTS: Propofol free fraction in blood was 1.2-1.7% at total concentrations ranging from 2.80 to 179 microM (0.5 to 32 microg ml(-1)). Fifty percent was bound to erythrocytes and 48% to serum proteins, almost exclusively to human serum albumin. In the clinical range of concentrations (0.5-16 microg ml(-1)) 40% of the molecules bound to erythrocytes are on the red blood cells membranes. No binding to lipoproteins occurred and binding to alpha1-acid glycoprotein was less than 1.5% CONCLUSIONS: We conclude that hypoalbuminaemia may increase propofol free fraction particularly during prolonged administration. Since propofol is non-restrictively cleared, no change in clearance is expected to occur, and the increase in free fraction will not be compensated by a parallel increase in clearance. It is also noted that many in vitro studies used concentrations 50 to 500 times the concentration expected to be encountered in the immediate cellular environment.