Renal tubular transport processes

A decline in the urinary excretion of uric acid to a level below the rate of production leads to hyperuricemia and an increased miscible pool of sodium urate. Almost all the urate in plasma is freely filtered across the glomerulus. The concentration of uric acid appearing in the urine is determined by multiple renal tubular transport processes in addition to the filtered load. Evidence favors a four-component model including glomerular filtration, tubular reabsorption, tubular secretion, and postsecretory reabsorption. ... 

Drugs that decrease renal clearance of uric acid through modification of filtered load or one of the tubular transport processes include diuretics, nicotinic acid, salicylates (less than 2 g/day), ethanol, pyrazinamide, levodopa, ethambutol, cyclosporine, and cytotoxic drugs. 

Probenecid appears to completely inhibit the renal tubular secretion of the active metabolite of oseltamivir via the anionic renal transporter process. Oseltamivir does not alter amoxicillin pharmacokinetics, suggesting minimal potential to inhibit the renal anionic transport process. Cimetidine, which inhibits the renal tubular secretion of drugs via the cationic secretion transport process, had no effect on oseltamivir. 

Nephrotoxicity Retention of the aminoglycosides by the proximal tubular cells disrupts calcium-mediated transport processes and results in kidney damage ranging from mild renal impairment to severe acute tubular necrosis which can be irreversible. 

Secretion is the transfer of materials from perimbular capillaries to the renal mbular lumen. Tubular secretion is mainly an active transport process. Usually only a few substances are secreted, unless they are present in great excess, or are natural poisons. 

There are biological processes, however, that involve saturable carrier or enzymatic systems, with a finite capacity for transport or catalysis. For instance, processes like active uptake at absorption sites, renal tubular secretion, or hepatic biotransformation of xenobiotics may become saturated at high exposure levels, yielding rates of disposition that are constant and independent of the concentration in blood. This is characteristic of zero-order kinetics. Biotransformations of ethanol in the liver and active tubular renal secretion of penicillin in urine are examples of biological processes that obey zero-order kinetics. Figure 7 illustrates the blood concentration... 

A renal clearance value greater than the GFR indicates that the drug is actively secreted, but a value less than the GFR does not preclude active secretion because tubular reabsorption takes place in the distal nephron. Competitive inhibition provides the only conclusive evidence that a transport process is carrier-mediated for example, probenecid decreases proximal tubular secretion of penicillin G. 

Figure 4S-6 Tubular reabsorptive mechanisms the major primary active transport processes in the proximal nephron.The renal tubular epithelium consists of a single layer of ceils. At the luminal side, adjacent cells are in contact (the tight junction), whereas toward the basal side of the cells, there are gaps between adjacent cells (lateral intercellular spaces). (From Lote CJ. Principles of renal pfiysio/ogy. 4tb ed. London Kluwer Academic Publishers, 2000 Chapter 4.)...

PAH is an organic anion that has been used extensively for the quantitation of renal plasma flow. PAH is approximately 17% bound to plasma proteins and is eliminated extensively by active tubular secretion. Because PAH elimination is active, saturation of the transport processes have historically been anticipated, at concentrations of PAH in plasma above 10 to 20 mg/L. Recently, Dowling and associates used a sequential infusion technique and only observed concentration-dependent renal clearance of PAH at concentrations above 100 mg/dL. Furthermore, PAH is also metabolized, possibly within the kidney, to A-acetyl-PAH, and the analytical method must be able to differentiate the parent compound from the metabohte if one desires to obtain an accurate assessment of RPF. Prescott and coworkers noted that the renal clearance of PAH alone decreases at low plasma concentrations, while the clearance of the acetyl metabolite increases. Further studies are necessary to evaluate the mechanisms and significance of these findings. The extraction ratio (ER) for PAH is 70% to 90% at plasma concentrations of 10 to 20 mg/L, hence the term effective renal plasma flow (ERPF) has been used when the clearance of PAH is not corrected for the extraction ratio or if it is assumed to be 1. Normal values for ERPF are about 650 160 mL/min for men and 600 150 mL/min for women. Children will reach normahzed adult values by 3 years of age, and ERPE will begin to decline as a function of age after 30 years, reaching... 

Passage of drugs into the CSF is controlled by the BCSFB. This barrier is created by ependymal cells of the choroid plexus, which function as an active transport system similar to the renal tubular epithelial cells. The inflammatory process associated with meningitis inhibits the active transport system of the choroid plexus. As in the active transport system in the kidney, the secretion of substances out of the choroid plexus also can be inhibited by the administration of probenecid. ... 

Proximal tubular injury due to nephrotoxicants occurs more frequently than other nephrotoxic effects, and this probably reflects a combination of the proportion of the total renal blood supply received by the renal cortex and the number of xenobiotics reabsorbed and excreted within the proximal tubule. Xenobiotics can alter or inhibit the transport processes of passive diffusion and/or carrier transporters for both anionic/base and cationic molecules. 

By extracting water from intracellular compartments, osmotic diuretics expand the extracellular fluid volume, decrease blood viscosity, and inhibit renin release. These effects increase RBF, and the increase in renal medullary blood flow removes NaCl and urea from the renal medulla, thus reducing medullary tonicity. Under some circumstances, prostaglandins may contribute to the renal vasodilation and medullary washout induced by osmotic diuretics. A reduction in medullary tonicity causes a decrease in the extraction of water from the DTL, which limits the concentration of NaCl in the tubular fluid entering the ATL. This latter effect diminishes the passive reabsorption of NaCl in the ATL. In addition, osmotic diuretics may also interfere with transport processes in the TAL. 

Probenecid markedly increased the AUC of the active metabolite of oseltamivir, but because of the large safety margin of oseltamivir, this increase is not considered to be clinically relevant. " Oseltamivir did not alter amoxicillin pharmacokinetics, and is therefore unlikely to interact with other renally secreted organic acids. Other drugs that are involved in the active anionic tubular secretion mechanism are also unlikely to interact. Cimetidine does not interact with oseltamivir, and other drugs that are inhibitors of the renal cationic secretion transport process are unlikely to interact. ... 

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