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 mug/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 mug/ml, gamma = 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.
Lee
Eun-Ho
EH
Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Lee
Soo-Han
SH
Park
Do-Yang
DY
Ki
Kyoung-Ho
KH
Lee
Eun-Kyung
EK
Lee
Dong-Ho
DH
Noh
Gyu-Jeong
GJ
D000328:Adult; D018686:Anesthetics, Intravenous / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D004655:Emulsions; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D009994:Osmolar Concentration; D010146:Pain / Q000139:chemically induced; D010147:Pain Measurement / Q000706:statistics & numerical data; D010316:Particle Size; D020442:Poloxamer; D011092:Polyethylene Glycols; D015742:Propofol / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D013228:Stearates; D013501:Surface-Active Agents
D018686:Anesthetics, Intravenous; D004655:Emulsions; D013228:Stearates; D013501:Surface-Active Agents; C466738:polyethylene glycol 660 12-hydroxy stearate; D020442:Poloxamer; D011092:Polyethylene Glycols; D001920:Bradykinin; D015742:Propofol