Tubular transport

Sulfonamides derived from sulfanilamide (p-arninoben2enesulfonainide) are commonly referred to as sulfa dmgs. Although several dmg classes are characterized by the presence of a sulfonamide function, eg, hypoglycemics, carbonic anhydrase inhibitors, saluretics, and tubular transport inhibitors, the antibacterial sulfonamides have become classified as the sulfa dmgs. Therapeutically active derivatives are usually substituted on the N nitrogen the position is generally unsubstituted. These features are illustrated by the stmctures of sulfanilamide (1) and sulfadiazine (2)... 

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. 

Cross, R.J. and Taggart, J.L. (1950). Renal tubular transport Accumlation ofp-aminohippurate by rabbit kidney slices. Amer. J. Physiol. 161 181-190. 

A plot of rate of transport against solute concentration in the tubule (Figure 8.3) shows fm, the tubular transport maximum to be analogous with Vmax for an enzyme, which is a maximum rate of solute transport across tubular cells. Assuming a fixed GFR, the point at which the plotted line begins to deviate from linearity, indicates that the substance exceeds a critical threshold concentration and begins to be excreted in the urine. When the plotted line reaches a plateau indicating that saturation point, that is tm has been reached, the rate of excretion is linear with increase in plasma concentration. The concept of fm as described here for tubular reabsorption applies equally well to carrier-mediated secretory processes. If the fm value for a particular is exceeded for any reason, there will be excretion of that solute in the urine. 

Excretion of a solute occurs if its rate of delivery to the tubules exceeds the 1, . Figure 8.3 tm tubular transport kinetics... 

Reduced hepatic mass reduced hepatic blood flow. Often decreased metabolizing isoenzyme activity. PseudocapiUar-ization of hepatic sinusoids Reduced renal plasma flow reduced glomerular filtration rate, altered tubular transport function... 

It is important to appreciate that these tubular transport mechanisms are not as well developed in the neonate as in the adult. In addition, their functional capacity may be diminished in the elderly. Thus, compounds normally eliminated by tubular secretion will be excreted more slowly in the very young and in the older adult. This age dependence of the rate of renal drug secretion may have important therapeutic implications and must be considered by the physician who prescribes drugs for these age groups. 

Compounds Secreted by Renal Tubular Transport Systems... 

During the first 3 h after Intravenous injection of 1 that followed administration of thiamine, urinary excretion of the oxime was about 12.7% below that during the corresponding period of the control experiment during the remainder of the run, it was 62.2% above that during the same period of the control experiment. Inasmuch as intravenous injection of 900 mg of sodium jg-aminohippurate with I decreased by only 6.3% the urinary excretion of I during the first 3 h after its administration, the tubular transport mechanisms for 1 and for jg-amino-hippurate probably are different. 

Age In newborn infants, the glomerular filtration rate and tubular transport is immature, which takes 5 to 7 months to mature. Also, the hepatic drug metabolism capacity is also inadequate (that is why chloramphenicol can produce grey baby syndrome ), and due to the higher permeability of blood brain barrier, certain drugs attain high concentration in the CNS. 

Spironolactone also increases Ca excretion through a direct effect on tubular transport. In relatively high concentrations, it can inhibit the biosynthesis of aldosterone. 

Spironolactone competitively inhibits the physiologic effects of the adrenocortical hormone aldosterone on the distal tubules, thereby producing increased excretion of sodium chloride and water, and decreased excretion of potassium, ammonium, titratable acid, and phosphate. Spironolactone is a potassium-sparing diuretic that has diuretic activity only in the presence of aldosterone, and its effects are most pronounced in patients with aldosteronism. Spironolactone does not interfere with renal tubular transport mechanisms, and does not inhibit carbonic anhydrase. 

Bourke RS, Chheda G, Bremer A, et al. Inhibition of renal tubular transport of methotrexate by probenecid. Cancer Res 1975 35 110-116. 

Shinosaki and Yonetani (1989), Shinosaki et al. (1994) performed stop-flow studies on tubular transport of uric... 

Shinosaki T, Yonetani Y (1989) Stop-flow studies on tubular transport of uric acid in rats. Adv Exp Med Biol 253A 293-300... 

Whelton A. Renal tubular transport and intrarenal aminoglycoside distribution. In Whelton A, Neu HC, editors. The Aminoglycosides. New York, Basel Marcel Dekker, 1982 191. 

Renal magnesium wasting is the main mechanism responsible for the hypomagnesemia associated with cisplatin (172), and it can be associated with enhanced tubular reabsorption of calcium and consequent hypocalciuria (173). This dissociation in the renal handling of calcium and magnesium is similar to what is found in Bartter s syndrome. The site of the renal tubular defect in these conditions is not known, but there is evidence that active renal tubular transport systems are disrupted. 

Transport mechanisms fortubular secretion of organic anions Tubular transport of organic cations ABC transporter family... 

An abundance of tubular epithelial enzymes involved in the tubular transport systems can be blocked, particularly in view of the highly concentrated solutes in the tubular fluid that may reach urinary/plasma concentration ratios exceeding 1000 in some cases. 

Roch-Ramel F, Besseghir K, Murer H. Renal excretion and tubular transport of organic anions and cations. In Handbook of physiology, section 8 renal physiology. Windhager EE (editor). Oxford University Press, NewYork/Oxford 1992 p. 2189-2262. Guggino SE, Aronson PS. Paradoxical effects of py razinoate and nicotinate on urate transport in dog renal microvillus membranes. J Clin Invest 1985 76 543-547. 

Van Crugten JT, Sallustio BC, Nation RL, Somogyi A. Renal tubular transport of morphine, morphine-6-glucuronide, and mor-phine-3-glucuronide in the isolated perfused rat kidney. Drug Metab Disp 1991 19 1087-1092. 

Tune BM. Renal tubular transport and nephrotoxicity of p-lactam antibiotics structure-activity relationships. Miner Electrolyte Metab1994 20 221-231. 

RennickB,ZiemniakJ, Smith l,TaylorM, Acara M. Tubular transport and metabolism ofcimetidine in chicken kidneys. Pharmacol ExpTher 1984 228 387-392. 

Bessighir K, Pearce LB, Rennick B. Renal tubular transport and metabolism of organic cations by the rabbit. Am J Physiol 1981 241 F308-F314. 

Limitations of the in vitro perfused juxtamedullary nephron preparation include 1) the availability of only a select population of juxtamedullary glomeruli near the inner surface of the kidney 2) underestimation of the contribution of flow in large vessels to preglomeru-lar resistance and 3) lack of characterization of tubular transport. 

Poola et al studied pentamidine toxicity in the isolated perfused rat kidney evaluating the effects of dosing and co-administration of tetraethylam-monium [150]. They also found that tubulotoxic-ity of pentamidine is dose-related and attributed to its degree of kidney sequestration caused by either the administration of a high dose of drug or by decreased tubular transport as caused by tetra-... 

Aminoacidurias may be primary or secondary. Primary disease is due to an inherited enzyme defect, also called an inborn error of metabolism. The defect is located either in the pathway by which a specific amino acid is metabolized or in the specific renal tubular transport system by which the amino acid is reabsorbed. Secondary aminoaciduria is due to disease of an organ, such as the liver, which is an active site of amino acid metabolism, or to generalized renal tubular dysfunction, or to protein-energy malnutrition. Specific inborn errors of metabohsm are discussed in more detail in Chapter 55. 

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