The overall objective of the proposed Program Project Grant is to define factors and elucidate mechanisms involved in 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. These goals will be achieved by a group of investigators including clinical pharmacologists, biochemical pharmacologists, as well as analytical and organic chemists. The role and importance of polymorphic hydroxylation os S- mephenytoin in the disposition of a number of related anticonvulsants and other drugs such as propranolol and carbaryl will be determined in normal subjects with different phenotypes. A new polymorphism of drug oxidation involving the N-hydroxylation of dapsone will be defined by population studies in different ethnic groups. Pedigree studies will be used to characterize the mode of inheritance and interphenotypic differences in disposition of dapsone and its metabolites will be determined. The effects of chronic liver disease on the disposition of debrisoquine and mephenytoin will be investigated to determine if these drugs can be used as measures of hepatic function in cirrhotic patients. Associations between oxidative and N- acetylator phenotypes and spontaneous diseases will be studied to determine whether the involved metabolic pathways are contributory to the etiology of the disease or are genetic markers. Diseases to be studied include bladder cancer, primary hepatoma, systemic lupus erythematosus, scleroderma and Parkinsonism. Clinical studies will evaluate the antiarrhythmic efficacy and toxicity of the oxidative metabolites of encainide. The clinical pharmacology of propafenone will be characterize, along with its active metabolite. Stereoselective aspects of encainide's disposition will be related to studies of the electrophysiologic activities of the enantiomers. In addition, comparative studies of antiarrhythmic agents will be undertaken in pediatric patients relative to established characteristics in adults. Of particular interest will be to determine whether apparent differences in sensitivity are related to pharmacokinetic or pharmacodynamic factors. The effects of various types of general and regional anesthesia on drug disposition will be studied in patients undergoing surgery. Comparisons will be made between different agents as well as techniques, and will provide new knowledge on drug interactions in the peri- and post-operative periods. The effects of combining quinidine with propranolol and also propafenone will also be established to determine changes in drug metabolism and effects dependent on oxidation status. Finally, the potential inhibition of metabolism of probes of oxidative metabolism by interferon will be investigated.
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