MOLECULAR ORGANIZATION OF RENAL ORGANIC CATION TRANSPORT

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Organic cations include a vast collection of pharmacologically important compounds. Indeed, drugs from a wide array of clinical classes-including antihistamines, skeletal muscle relaxants, antiarrythmics, and beta- adrenoceptor blocking agents-are organic cations (Ocs). The kidney plays a critical role in clearing these compounds from the body, thereby influencing their clinical effectiveness and posing the potential for undesirable interactions at the level of the excretory process. A general model of renal OC secretion has been in place for almost 20 years, but it does not include the molecular mechanisms of the processes involved and, therefore lacks the basis upon which to build a predictive model of the renal secretion of cationic drugs. The recent cloning of several 'candidate transporters' believed to play a role in renal OC transport )OCT1, OCT2, OCTN1, and OCTN2) makes possible development of a molecularly-based secretory model, provided that answers to several critical questions are obtained: (1) Where are these transporters expressed in the kidney; (2) How (mechanistically) do they contribute to OC secretion; and (3) What substrates are handled by each of the several (current) candidate transporters? Finally, (4) Can the ensemble behavior of these processes, based upon their measured characteristics, account for the secretory activity observed in proximal tubules? To answer these questions we have developed an experimental plan that will examine the above listed characteristics of the candidate transporters The approach involves comparison of results obtained with intact renal tubules with those obtained using single cloned transport proteins. The latter system permits examination of the properties of single transporters, while the former provides the only means to assess how the integrated activity of a suite of processes influences net transepithelial substrate movement. The cloned transporters will include the human orthologs of the four transporters and, also, the rabbit orthologs of each process. The latter set of observation will be used to validate use of the intact tubule systems we will employ to test a model of cationic drug secretion based upon the individual characteristics of each OC transporter. This study will be the first to offer an integrated view of the several processes that must work together to effect renal secretion of cationic drugs and thereby establish the necessary base for developing a therapeutically useful model of renal drug secretion.