Propranolol and the more recently introduced beta-adrenergic blocking agents are considered the drugs of choice in these treatment of hypertension associated with various forms of renal diseases. Drug surveillance studies have revealed a higher incidence of adverse drug reactions with propranolol in patients with renal dysfunction than in patients with normal renal function. Part of the reason for the increased risk of adverse drug reactions may be related to the markedly elevated circulating levels of propranolol due to a diminished first-pass hepatic extraction of orally-administered propranolol in renal failure. Uremia-induced inhibition of metabolic clearance has been reported with several of the newer beta-blockers and various other drug substrates that are extensively metabolized in the liver. The continuing goal of this grant project is to elucidate the mechanism(s) responsible for the apparent inhibition of hepatic extraction of propranolol in uremia. Much of the investigation has been conducted in experimental models of renal failure in rats. During the last project period, we provided evidence that the decrease in hepatic extraction of (-)-propranolol is due to the presence of a circulating endogenous inhibitor(s) in uremic rat blood. Other investigators have also presented evidence of an intrinsic heptocellular defect in uremic rat liver. The proposed research in the current application is aimed at: (i) identifying the exact hepatocellular uptake and metabolic processes that are inhibited during uremia; (ii) isolating and characterizing the inhibitory factor in uremic rat blood; and (iii) seeking supportive evidence for the existence of an endogenous inhibitor of propranolol clearance in the circulation of chronic renal failure patients. Freshly isolated rat hepatocytes will be used to investigate the effects of uremia on plasma membrane transport, intracellular binding and cytochrome P-450 mediated metabolism of (-)-propranolol. Serum from normal and renal failure rats will be fractionated by a variety of biochemical techniques to isolate and eventually identify the putative uremic inhibitor(s). Lastly, plasma obtained form end-stage renal failure patients will be tested for inhibitory activity by an in vitro rat hepatocyte bioassay. These studies are expected to provide some much needed understanding of the factors affecting drug metabolism in uremia, which may prove useful in guiding the selection of drugs in renal failure patients.
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