the objective of this proposed program project is to continue to a coordinated, multidisciplinary program of research in the clinical pharmacology of drugs that are used frequently in medical practice. The research will have a central pharmacokinetic orientation and will attempt to elucidate the physiological basis of drug distribution and to correlate both the distribution properties of some centrally acting drugs with the kinetics of their central nervous system effects. Participants in the proposed research have expertise in pharmacokinetics, drug metabolism and analytical methods, nephrology, anesthesiology and cardiac surgery. The five projects detailed in this application deal with some aspect of the kinetics of drug distribution. In the first project, we will attempt to provide a rationale for the 3-compartment mamillary models that are often used to model the distribution of some drugs. Our hypothesis is that for drugs in which the central compartment represenrs intravascular space, there is a correspondence between the peripheral compartments of the pharmacokinetic model and a parallel circuit model that has been used by some investigators to analyze hemodynamic changes in the systemic circulation. We intend to verify this hypothesis and to analyze the contributions of blood flow and diffusion to intercompartmental clearance. We plan then to test the applicability of this approach in evaluating pharmacokinetic changes that we have previously found during hemodialysis, in analyzing the effects of hemodynamic changes on lidocaine distribution, and in comparing the transcapillary diffusion rates of inulin and gallamine with their free-water diffusion coefficients. In an additional project, we plan to extend observations made by the principal investigator on the pharmacokinetics of intrathecally administered drugs to an analysis of the distribution kinetics and cerebrospinal fluid clearance of intrathecally administered morphine. We will attempt to correlate these results with measurements of respiratory depressant effect.
