FORMULATION-DEPENDENT PHARMACOKINETICS AND PHARMACODYNAMICS OF PROPOFOL IN RATS

Propofol, a highly lipophilic anaesthetic, is commercially formulated as a lipid emulsion (diprivan) for intravenous use. This formulation i s characterized by rapid onset and offset of effect after rapid intrav enous administration and an effect-site equilibration half-life (t1/2 k(EO)) of 1.7 min in rats. Paradoxically these characteristics are usu ally associated with relatively water-soluble anaesthetics. To test th e influence of the formulation on propofol pharmacokinetics, effect-si te equilibration kinetics and pharmacodynamics we performed a pharmaco kinetic-pharmacodynamic study of propofol in chronically instrumented rats after administration in a lipid-free formulation. In this report we present the results of this study and compare these results with pr evious data obtained with rats receiving propofol in the emulsion form ulation. Compared with the emulsion formulation the distribution volum es (Vd(C) and Vd(SS)> were significantly higher but the t1/2 k(EO) (2. 0 min) was similar for the lipid-free formulation. The concentration-e ffect relationship was biphasic. Propofol effect-site concentrations r equired to achieve 50% activation, peak activation, 50% inhibition of peak activation effect and maximum inhibition were significantly lower , indicating a higher apparent steady-state potency for the lipid-free formulation compared with the emulsion formulation. The evanescent ch aracteristics of propofol's effect-time-course disappeared when the an aesthetic was administered in the lipid-free formulation. These result s suggest that the nature of the formulation can profoundly influence the clinical characteristics of intravenously administered drugs by mo difying the pharmacokinetics or pharmacodynamics or both.