Physicochemical properties, pharmacokinetics, and pharmacodynamics of a reformulated microemulsion propofol in rats

Background: A newly developed microemulsion propofol consisted of 10% purified poloxamer 188 and 0.7% polyethylene glycol 660 hydroxystearate. The authors studied the physicochemical properties, aqueous free propofol concentration, and plasma bradykinin generation. Pharmacokinetics and pharmacodynamics were also evaluated in rats. Methods: The pH, particle size, and osmolarity of microemulsion propofol were measured using a pH meter, particle size analyzer, and cryoscopic osmometer, respectively. The aqueous free propofol and plasma bradykinin were measured by a dialysis method and radioimmunoassay, respectively. Microemulsion propofol was administered by zero-order infusion of 0.5, 1.0, and 1.5 mg • kg • min for 20 min in 30 rats. The electroencephalographic approximate entropy was used as a surrogate measure of propofol effect. Results: The pH, osmolarity, and particle size of microemulsion propofol are 7.5, 280 mOsm/l, and 67.0 ± 28.5 nm, respectively. The aqueous free propofol concentration in microemulsion propofol was 63.3 ± 1.2 μg/ml. When mixed with human blood, microemulsion propofol did not generate bradykinin in plasma. Although microemulsion propofol had nonlinear pharmacokinetics, a two-compartment model with linear pharmacokinetics best described the time course of the propofol concentration as follows: V1 = 0.143 l/kg, k10 = 0.175 min, k12 = 0.126 min, k21 = 0.043 min. The pharmacodynamic parameters in a sigmoid Emax model were as follows: E0 = 1.18, Emax = 0.636, Ce50 = 1.87 μg/ml, γ = 1.28, ke0 = 1.02 min. Conclusions: Microemulsion propofol produced a high concentration of free propofol in the aqueous phase. For the applied dose range, microemulsion propofol showed nonlinear pharmacokinetics.