Concentration-EEG effect relationship of propofol in rats

Propofol is a unique highly lipid-soluble anesthetic that is formulated in a fat emulsion (Diprivan) for intravenous (iv) use. It has the desirable properties of rapid onset and offset of effect following rapid iv administration and minimal accumulation on long-term administration. Based on physicochemical properties and preliminary brain solubility data, propofol should have an extended effect-site turnover and a resulting prolonged effect. However, a preliminary study in humans has reported a rapid blood-brain equilibration half-time (T-1/2 k(E0)) Of only 2.9 min. We used a chronically instrumented rat model to examine the unique disposition and electroencephalographic (EEG) pharmacodynamics of propofol. Although the pharmacokinetics were variable, there was low interindividual variability in the concentration-EEG effect relationship. The duration of EEG sleep was 26 (+/-44% CV) min following 11-15 mg/kg doses of propofol. The T-1/2 k(E0) was 1.7 (+/-32%) min. Apparent effect-site concentrations of 0.5-1 mu g/mL were required to maintain sleep in rats. Like other general anesthetics, the concentration-EEG effect relationship of propofol is biphasic. At a propofol concentration of 0.6 (+/-35%) mu g/mL, the number of EEG waves/s was maximal at 175% of baseline awake state. Further increases in the concentration of propofol depressed EEG activity until complete suppression occurred at 7 (+/-22%) mu g/mL.