The overall objective of the proposed Program Project Grant is to define factors and elucidate mechanisms involved in the interindividual variability in response following drug administration. The basic and clinical knowledge obtained from this research will provide a basis for the rational and safe use of drugs. The goals will be achieved by a group of investigators including clinical pharmacologists working in close collaboration with biochemical pharmacologists, as well as analytical and organic chemists. The population distribution, mode of inheritance and the pharmacological/toxicological consequences of genetic variability in drug elimination, especially that of a discontinuous nature, is of major interest, In particular, the deficient metabolism of the anticonvulsant, mephenytoin and a new antiarrhythmic agent, encainide, and the impaired elimination of the hypoglycemic tolbutamide will be studied. The involvement of a genetic factor in the development of arylamine-induced bladder cancer will also be investigated. The role of active and reactive metabolites in the efficacy and toxicity of antiarrhythmic agents will be investigated. Animal and clinical studies will be used to define the relative contributions of parent and metabolites to the overall pharmacological effects of encainide and quinidine. In addition, the involvement of a reactive metabolite(s) in the lupus-like syndrome resulting from procainamide therapy will be investigated. The effects of inhalation anesthesia on the distribution and metabolism of drugs will be studied in animal models. Specific questions that will be addressed include differences between anesthetics, such as halothane, enflurane, isoflurane and nitrous oxide, and the differential sensitivity of the disposition of various types of drugs to such agents. The contribution of alpha2 adrenoreceptors to the regulation of autonomic function in man will be systematically investigated, using yohimbine as a tool. the drug's clinical pharmacology will be defined in both normal subjects and patients with autonomic dysfunctions, and a model for a clinically evaluating this receptor sub-type will be developed. It is also planned to investigate the factors regulating beta adrenoreceptor affinity in man and to define the abnormalities produced by hypertension and thyrotoxicosis.