An evaluation of the effect of probenecid on the urinary elimination of losartan , a drug to control high blood pressure, and its E-3174 metabolite. The hypothesis of this study is that the secretion of losartan and its metabolic waste, E-3174, provides a major route of elimination. The effect of losartan on the excretion of uric acid may also be linked to losartan's proximal tubular handling. Probenecid, an inhibitor of renal transport, should block the secretion of losartan and E-3174 as well as alter the excretion of uric acid in the urine.
The specific aims of this study are; 1) to determine the way the body metabolizes, distributes, absorbs, and excretes the drug losartan and E-3174 with and without probenecid in normal volunteer subjects, 2) To define the urine elimination profile of uric acid to losartan with and without the administration of probenecid, 3) to further characterize the early excretion of potassium which attends the administration of losartan, and 4) to determine the cyclical pattern of serum uric acid in placebo-treated subjects who are also subjected to losartan therapy with its expected effect on serum uric acid. The volunteers for this study will be men or women below the age of 45 years. The subjects will have had normal screening exams, screening chemistries, and hematology panels, and will not be requiring medication on a chronic basis. Female subjects will have negative pregnancy tests. Before the start of the study, volunteers will be instructed to eat a special diet to be consumed for 72 hours. On the day before the onset of the study, a 24-hour urine sample will be taken. Volunteers will be randomized into four different treatment groups, each with a different dose of medications or a placebo. Predetermined meals will be consumed during the study. Subjects will be given 8 ounces of water to drink before dosing and at two hours after dosing to facilitate urination and urine collection. The study will require hospitalization for four separate days and nights over an eight-week time span, during which time multiple blood and urine samples will be obtained. Each 24-hour hospitalization will be followed by a 24-hour outpatient portion of the study, where urine will continue to be collected.
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