Significant progress has been made in understanding the subcellular mechanisms involved in the metabolism of drugs. In contrast, little is known about the mechanisms involved in the other major pathway of drug elimination, renal excretion. The organic cation transport system of the renal proximal tubule is responsible for the active secretion from the body of many important basic drugs including procainamide, cimetidine, morphine and certain beta adrenoreceptor blocking agents. The overall goals of the proposed studies are to elucidate the cellular mechanisms of the organic cation transport system and to determine the biologic relevance of these findings to the mechanisms of transport of basic drugs. The mechanisms of the system will be investigated using a model organic cation, N1-methylnicotinamide (NMN).
The specific aims of these studies are to: (1) characterize the transport of NMN in the luminal and antiluminal membrane of the renal proximal tubule; (2) test ion gradients as possible driving forces for organic cation transport in the two membranes; (3) elucidate the electrogenecity of organic cation transport in the antiluminal and luminal membrane; (4) determine whether the transport systems in both membranes function as specific pores or mobile carriers; (5) delineate the specific functional groups that are essential for organic cation transport in the two membranes; In addition, the mechanisms of transport of model drug, procainamide, will be studied. Luminal and antiluminal membrane vesicles will be prepared from rabbit renal cortex. Isotopic studies of 3H-NMN and 3H-procainamide will be studied. Michaelis-Menten parameters of each of the compounds in both membranes will be determined. The effect of various ion gradients on uptake of 3H-NMN will be determined. In addition, the studies will make use of pH-gradient fluorescent probes and potential sensitive probes. Modifying reagents will be used to determine the relevant functional groups for transport in both membranes. Clinically, many important drugs are eliminated from the body by the organic cation transport system. Knowledge of the mechanisms involved in the system will enhance the rational use of these compounds. The studies with procainamide will elucidate the relevance of these mechanisms to a clinically important drug. These studies will ultimately lead to a more sophisticated knowledge of the renal elimination of drugs.
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