The objective of this project is to continue a 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 consist of studies to elucidate the physiological basis of drug distribution, to measure bioavailability in different patient groups, and to characterize theophylline kinetics in pregnancy. Participants in the proposed research have expertise in pharmacokinetics, drug metabolism and analytical methods, anesthesia, obstetrics and gynecology, cardiac surgery, nephrology and nuclear medicine. Five of the six projects in this application deal with some aspect of the kinetics of drug distribution. The first project consists of studies of the rationale for the 3-compartment mammillary models that are often used to model drug distribution. At this point, it is evident for some drugs that the central compartment represents intravascular space and that the rapid and slow equilibrating peripheral compartments result from heterogeneity in transcapillary exchange rates. The second project will characterize hemodynamically-mediated changes that may reduce the efficiency of hemodialysis. Research in the third project will focus on non-distributive blood flow that is observed when gallamine is co-administered with inulin and will attempt to determine if this represents a gallamine-mediated increase in arteriovenous anastomotic blood flow. The fourth project is designed to elucidate the nature of the extra-vascular initial distribution space of some barbiturate anesthetics, to see if midazolam also exhibits this distribution pattern, and to confirm that the volume of this space falls with age and increases the risk of anesthesia induction with barbiturates. A novel stable isotope method that we developed will be applied in the fifth project to study N-acetylprocainamide bioavailability in elderly patients and in patients with renal failure and congestive heart failure. The sixth project consists of pharmacokinetic studies with theophylline, a drug that appears to distribute initially in extracellular fluid space. Changes in theophylline kinetics will be evaluated serially during and after pregnancy, and the rate of transplacental theophylline transfer will be characterized.
