The overall objective of the proposed Program Project Grant continues to be the definition of factors and elucidation of 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 development and safe use of drugs. These goals will be achieved by a group of investigators with expertise and interest in clinical pharmacology, molecular and biochemical pharmacology, and analytical and organic chemistry. The role and importance of racial/ethnic origin in drug disposition and pharmacologic effects is emerging as an important factor in drug evaluation and clinical use, given the increasing diversity of the U.S. population and the worldwide availability of drugs. Studies are proposed to investigate inter-racial differences between Caucasians, Blacks, Chinese and Indians using a number of drugs as probes for P450IICMP and P450IIIA4-mediated pathways of metabolism. Peptides have considerable potential as therapeutic agents but challenges exist in their delivery to the site of action because of the impermeability of many biological membranes and rapid hepatic elimination. Studies will be undertaken with oligopeptides of demonstrated orally effectiveness, which are extensively excreted in the bile, in order to identify and characterize the mechanisms of carrier- mediated transport at the brush-border and basolateral membranes of the intestine and the sinusoidal and canalicular membranes of the liver. Psychoactive drugs structurally related to buspirone are emerging as potentially valuable therapeutic agents in the treatment of anxiety and psychosis. The contribution of drug metabolism to the often large interindividual differences in responsiveness to such agents and factors involved in the often widely different pattern of metabolism are, however, unclear. Studies will be undertaken to identify the individual enzymes involved in such metabolism and to investigate structural factors that determine the extent and involvement of specific pathways of metabolism. Drugs that either activate or block potassium channels are becoming increasingly used in the treatment of several important and common human disease. Clinical investigations will be pursued to assess the consequences of combination of such drugs in modulating antihypertensive, hypoglycemic or electrophysiological effects. Studies will also be directed towards defining the role and importance of sympathetic activation in the QT interval prolonging action of Class III antiarrhythmic agents. It is also proposed to examine the electrophysiological characteristics of terfenadine's enantiomers in order to determine the importance of chirality in the unpredictable occurrence of torsades de pointes in patients administered this and other widely used """"""""non-sedating"""""""" antihistamines.
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