This is a program project application to support multidisciplinary research on aspects of the kinetics of drug distribution, transcellular transport and elimination that are related to clinical pharmacology. The clinical orientation of the proposed research ranges from the development of drugs for children with neuroblastoma, to lidocaine treatment of ventricular arrhythmias in older patients. Studies pertinent to patients of all ages are also included that focus on hemodialysis kinetics, attenuation of cellular resistance to antineoplastic drugs, and the significance of the pulmonary distribution of intravenous anesthetics. Three of the four projects in this application extend our basic studies on the kinetics of drug distribution within the body. In Project 1, we will conduct clinical studies with inulin and urea, using them as marker compounds to analyze the kinetics of transcapillary exchange. We also will-ascertain the extent to which hemodialytic removal of urea is affected by dialysis-associated changes in its intercompartmental clearance. In Project 4, we will analyze the pulmonary uptake kinetics of fentanyl and alfentanil and examine the effect that propranolol has on fentanyl pulmonary uptake and electroencephalographic effects. The remaining projects will examine aspects of the transcellular distribution of antineoplastic agents, both as they relate to P-glycoprotein-mediated resistance to doxorubicin (Project 2) and to the enhancement of selectivity of purine nucleoside analogues, which depend on kinetically different transport systems for entering neuroblastoma and bone marrow cells (Project 3). Participating investigators have expertise in the basic areas of pharmacokinetics, drug metabolism and analytical chemistry, cardiovascular physiology, biochemistry and cell biology, and in the clinical fields of anesthesia, cardiology, nephrology, oncology, pathology, pediatrics and perinatal medicine.
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