BEHAVIORAL-EFFECTS AND PHARMACOKINETICS OF PROPOFOL IN RATS SELECTED FOR DIFFERENTIAL ETHANOL SENSITIVITY

High- and low-alcohol sensitivity (HAS and LAS) rats have been selecte d for their differences in ethanol-induced sleep time. The rats also d iffer in sensitivity to pentobarbital, halothane, isoflurane, and enfl urane. To determine if this sensitivity extended to propofol, the anes thetic requirements were measured. In this study, the sleep time and t he tissue levels of propofol at awakening, as well as the pharmacokine tics, were evaluated. Propofol was administered intravenously. For one group of rats, sleep times were measured; blood and brain samples wer e taken at awakening. Blood samples were collected in another group of rats at frequent intervals from 0 to 90 min after injection. Propofol concentration of the samples was determined by gas chromatography. Th e pharmacokinetic analysis was performed using a nonlinear least-squar es regression program. Sleep time was not different; however, blood an d brain propofol levels at awakening showed a small, but significant d ifference between HAS and LAS rats. Propofol blood concentration-time curve data were fitted to a three-compartment model. Pharmacokinetic p arameters were also not different between the rat lines. However, slee p time was 50% longer in female rats than male rats in both strains (p < 0.0001). The rates of propofol clearance were slower in female rats , because of different rates of disappearance from the second compartm ent. The observations suggest that the genetic selection for ethanol s ensitivity selection for propofol sensitivity was not nearly as intens e and presumably involves some different genes. These two central nerv ous system depressants would seem to differ significantly in their mec hanism of action. The differential sleep times produced by propofol in the male and female rats are caused by pharmacokinetic differences.