Renal transport mechanisms

Osmotic diuretics are the only group of compounds whose action is not associated with a reaction to corresponding receptors, or with direct blocking of any renal transport mechanism. Pharmacological activity of this group depends solely on the osmotic pressure... 

KosoglouT,Vlasses PEI. Drug interactions involving renal transport mechanisms anoverview. CICP Ann Pharmacother 1989 23 116-22. 

RENAL TRANSPORT MECHANISMS DIURETIC DRUG GROUPS... 

The indicator dilution technique possesses the disadvantage of requiring arterial injection and ureteral cannulation in the anesthetized animal. On the other hand, it is rapid and consumes relatively little solute, thus permitting convenient and repeated measurements of relative clearances. Care must be taken in all renal transit experiments to use sufficiently low bolus concentrations of fhe fesf solute so that even at its peak plasma concentration renal transport mechanisms do not become saturated. 

When addressing excretion from the kidneys glomeruli, the principles of passive membrane diffusion are again applicable. Chemicals which are ionized (water soluble) and those that are non-ionized (lipid soluble) are reabsorbed. There are also active renal transport mechanisms, such as those in the proximal tubules for organic acids and organic bases. Toxins bound to plasma proteins, too large for renal glomerular filtration, are often excreted in bile. Active mechanisms exist to transport chemicals from plasma to liver and from liver to bile for excretion. 

A number of genetic diseases that result in defects of tryptophan metabolism are associated with the development of pellagra despite an apparently adequate intake of both tryptophan and niacin. Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan, resulting in large losses due to intestinal malabsorption and failure of the renal resorption mechanism. In carcinoid syndrome there is metastasis of a primary liver tumor of enterochromaffin cells which synthesize 5-hydroxy-tryptamine. Overproduction of 5-hydroxytryptamine may account for as much as 60% of the body s tryptophan metabolism, causing pellagra because of the diversion away from NAD synthesis. 

Assuming the capsular pressures opposing the movement of water out of the blood and into the top of the nephron are constant, the net filtration pressure is due largely to the blood pressure. Any fall in blood pressure can have a dramatic effect on the efficiency of filtration and therefore clearance of waste materials. So important is the pressure within the renal vasculature that the kidney is critical in regulating systemic blood pressure via the renin-angiotensin-aldosterone (RAA) axis, a physiological process which relies on transport mechanisms within the renal tubules. 

Active renal elimination of an organic anion. The transport mechanism is in the peritubular portion of the membrane of the proximal tubular cell. 

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. 

Renal handling of uric acid. Uric acid may be actively reabsorbed from the ultrafiltrate following its glomerular filtration or it may be secreted from the blood across the basolateral membrane into the proximal tubular cell. Both passive and active transport mechanisms are involved in the handling of urate. Uricosuric drugs at appropriate doses interfere with these processes. 

This chapter is divided into three sections. The first section covers renal tubule transport mechanisms. The nephron is divided structurally and functionally into several segments (Figure 15-1, Table 15-1). Many diuretics exert their effects on specific membrane transport proteins in renal tubular epithelial cells. Other diuretics exert osmotic effects that prevent water reabsorption (mannitol), inhibit enzymes (acetazolamide), or interfere with hormone receptors in renal epithelial cells (aldosterone receptor blockers). The physiology of each segment is closely linked to the basic pharmacology of the drugs acting there, which is discussed in the second section. Finally, the clinical applications of diuretics are discussed in the third section. 

RENAL TUBULE TRANSPORT MECHANISMS Proximal Tubule... 

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. 

In the kidney, filtered solutes such as glucose are recovered from the forming urine primarily by active transport mechanisms in the renal tubules. As in the small intestine, glucose is removed from the tubule lumen by SGLT1 and exits across the basolateral membrane via GLUT2. The low affinity of GLUT2 makes flow from the blood into the tubule epithelial cells minimal at normal blood glucose concen-... 

Sitagliptin (1) demonstrated plasma half-lives in rats, dogs, and rhesus monkeys of 1.7-4.9 h, and oral bioavailabilities of 68 100%. In rats and monkeys, clearance of 1 was relatively high (60 and 28 mL/min/kg, respectively) and was lower in dogs (6 mL/mg/kg).15 In rats and dogs, 1 was systemically cleared primarily by renal elimination of intact parent drug, with additional contributions from biliary excretion (rats) and metabolism (minor in both species).23 In rats, data suggest that active transport mechanisms are involved in the renal elimination of 1. 

These include mannitol and sorbitol which act mainly in the proximal tubules to prevent reabsorption of water. These polyhydric alcohols cannot be absorbed and therefore bind a corresponding volume of water. Since body cells lack transport mechanisms for these substances (structure on p.175), they also cannot be absorbed through the intestinal epithelium and thus need to be given by intravenous infusion. The result of osmotic diuresis is a large volume of dilute urine, as in decompensated diabetes melli-tus. Osmotic diuretics are indicated in the prophylaxis of renal hypovolemic failure, the mobilization of brain edema, and the treatment of acute glaucoma attacks (p. 346). 

Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan and other large neutral amino acids. The result is that the intestinal absorption of free tryptophan is impaired, although dipeptide absorption is normal. There is a considerable urinary loss of tryptophan (and other amino acids) as a result of the failure of the normal reabsorption mechanism in the renal tubules - renal aminoaciduria. In addition to neurological signs that can be attributed to a deficit of tryptophan for the synthesis of serotonin in the central nervous system, the patients show clinical signs of pellagra, which respond to the administration of niacin. 

CSF if the meninges are inflamed. Penicillins are organic acids and their rapid clearance from plasma is due to secretion into renal tubular fluid by the anion transport mechanism in the kidney. Renal clearance therefore greatly exceeds the glomerular filtration rate (127 ml/min). The excretion of penicillin can be usefully delayed by concurrently giving probenecid which competes successfully for the transport mechanism. Dosage of penicillins may should be reduced for patients with severely impaired renal function. 

Naasani I, Sugawara M, Kohayashi M, Iseki K, and Miyazaki K. Transport mechanism of ceftihuten, a dianionic cepherm, in rat renal hnish-horder Membrane. Pharm. Res. 1995 12 605-608. 

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