Kidney active transport

Active Transport. Maintenance of the appropriate concentrations of K" and Na" in the intra- and extracellular fluids involves active transport, ie, a process requiring energy (53). Sodium ion in the extracellular fluid (0.136—0.145 AfNa" ) diffuses passively and continuously into the intracellular fluid (<0.01 M Na" ) and must be removed. This sodium ion is pumped from the intracellular to the extracellular fluid, while K" is pumped from the extracellular (ca 0.004 M K" ) to the intracellular fluid (ca 0.14 M K" ) (53—55). The energy for these processes is provided by hydrolysis of adenosine triphosphate (ATP) and requires the enzyme Na" -K" ATPase, a membrane-bound enzyme which is widely distributed in the body. In some cells, eg, brain and kidney, 60—70 wt % of the ATP is used to maintain the required Na" -K" distribution. 

Materials may be absorbed by a variety of mechanisms. Depending on the nature of the material and the site of absorption, there may be passive diffusion, filtration processes, faciHtated diffusion, active transport and the formation of microvesicles for the cell membrane (pinocytosis) (61). EoUowing absorption, materials are transported in the circulation either free or bound to constituents such as plasma proteins or blood cells. The degree of binding of the absorbed material may influence the availabiHty of the material to tissue, or limit its elimination from the body (excretion). After passing from plasma to tissues, materials may have a variety of effects and fates, including no effect on the tissue, production of injury, biochemical conversion (metaboli2ed or biotransformed), or excretion (eg, from liver and kidney). 

Because bretylium is poody absorbed from the GI tract (- 10%), it is adrninistered iv or im. Very litde dmg is protein bound in plasma. Bretylium is taken up by an active transport mechanism into and concentrated in postganglionic nerve terminals of adrenergicahy innervated organs. Peak plasma concentrations after im injections occur in about 30 min. Therapeutic plasma concentrations are 0.5—1.0 p.g/mL. Bretylium is not metabolized and >90% of the dose is excreted by the kidneys as unchanged dmg. The plasma half-life is 4—17 h (1,2). 

Excretion via the kidney can be a straightforward question of glomerular filtration, followed by passage down the kidney tubules into the bladder. However, there can also be excretion and reabsorption across the tubular wall. This may happen if an ionized form within the tubule is converted into its nonpolar nonionized form because of a change in pH. The nonionized form can then diffuse across the tubular wall into plasma. Additionally, there are active transport systems for the excretion of lipophilic acids and bases across the wall of the proximal tubule. The antibiotic penicillin can be excreted in this way. 

Sodium SGLTl -dependent unidirectionai transporter Small intestine and kidney Active uptake of glucose from lumen of intestine and reabsorption of glucose in proximal tubule of kidney against a concentration gradient... 

Because the transport of sodium is an active process, it is used to accumulate NaCl in the interstitial fluid of the medulla. In fact, this activity is involved in the initial establishment of the vertical osmotic gradient. Furthermore, sodium is actively transported out of the tubular epithelial cells up its concentration gradient until the filtrate is 200 mOsm/1 less concentrated than the surrounding interstitial fluid. This difference between the filtrate and the interstitial fluid is referred to as the horizontal osmotic gradient. Because the filtrate at the end of the Loop of Henle has an osmolarity of 100 mOsm/1, the kidneys have the ability to produce urine that is significantly more dilute than the plasma. 

Some laboratories have found an alternative to the short-term cultures by using cell lines other than Caco-2 cells. The most popular of these is Madin-Darby canine kidney (MDCK) cells, an epithelial cell line from the dog kidney. MDCK cells have been suggested to perform as well as Caco-2 cells in studies of passive drug permeability [56]. These cells have also been used to optimise the conditions for studies of low-solubility drugs [53]. However, as noted previously, the active transport processes of this cell line can be quite different to those of Caco-2 cells [28-30], Another cell line that only requires short-term culture is 2/4/A1, which is a conditionally immortalised rat intestinal epithelial cell line [86]. The 2/4/A1 cell line is discussed in Section 4.3.2.2 below. 

Inui, K., Saito, H. and Hori, R. (1985). H+ gradient-dependent active transport of tetaethyl-ammonium cation in apical-membrane vesicles isolated from kidney epithelial cell line LLC-PK Biochem. J. 227 199-203. 

The interplay of kidney-selective transport and/or kidney-selective activation is well illustrated by the prodrug y-glutamyl sulfamethoxazole (6.24, R=H) and some A-acyl-y-glutamyl derivatives (6.24, R=acyl) [41], y-Glu-sulfamethoxazole, indeed, released sulfamethoxazole at high rates in kidney homogenates, whereas other organs showed low or negligible activity. Its... 

Any mechanism suggested for carrying out the active transport of glucose in the kidney must provide at least this much work. 

In vitro stndies have shown that there are distinct transport systems for both baso-lateral and apical uptake of nicotine (Takami et al. 1998). Nicotine has been shown to be actively transported by kidney cells, most likely by the organic ion transporter OCT2 (Zevin et al. 1998 Urakami et al. 1998). Cimetidine decreases renal clearance of nicotine by 47% in nonsmoking volunteers (Bendayan et al. 1990). This is consistent with the inhibition of basolateral uptake by cimetidine detected in vitro. Mecamylamine reduces renal clearance of nicotine in smokers dosed with intra-venons nicotine when urine is alkalinized, but not when nrine is acidified (Zevin et al. 2000). 

As lithium is an alkaline earth metal which readily exchanges with sodium and potassium, it is actively transported across cell membranes. The penetration of kidney cells is particularly rapid, while that of bone, liver and brain tissue is much slower. The plasma CSE ratio in man has been calculated to be between 2 1 and 3 1, which is similar to that found for the plasma red blood cell (RBC) ratio. This suggests that the plasma RBC ratio might be a useful index of the brain concentration and may be predictive of the onset of side effects, as these appear to correlate well with the intracellular concentration of the drug. 

Some cells couple the pure transport forms discussed on p. 218—i.e., passive transport (1) and active transport (2)—and use this mechanism to take up metabolites. In secondary active transport (3), which is used for example by epithelial cells in the small intestine and kidney to take up glucose and amino acids, there is a symport (S) located on the luminal side of the membrane, which takes up the metabolite M together with an Na" ion. An ATP-dependent Na transporter (Na /lC ATPase see p. 350) on the other side keeps the intracellular Na+ concentration low and thus indirectly drives the uptake of M. Finally, a uniport (U) releases M into the blood. 

Sodium ions. Controlled resorption of Na"" from the primary urine is one of the most important functions of the kidney. Na" resorption is highly effective, with more than 97% being resorbed. Several mechanisms are involved some of the Na" is taken up passively in the proximal tubule through the junctions between the cells (paracellularly). In addition, there is secondary active transport together... 

Colchicine is rapidly absorbed after oral administration and tends to concentrate in the spleen, kidney, liver, and gastrointestinal tract. Leukocytes also avidly accumulate and store colchicine even after a single intravenous injection. Since colchicine can accumulate in cells against a concentration gradient, it is postulated that an active transport process may be involved in its cellular uptake. The drug is metabolized, primarily in the liver, by deacetylation. Fecal excretion plays a major role in colchicine elimination, since it and its metabolites are readily secreted into the bile. Only about 15 to 30% of the drug is eliminated in the urine except in patients with liver disease urinary excretion is more important in these individuals. 

The mechanisms of transfer of molecules and ions across the wall of tubules are more complicated than in the artificial apparatus. In addition to osmosis and simple passive transport viz., ordinary downhill mass transfer due to concentration gradients), renal mass transfer involves active transport viz., uphill mass transport against gradients). The mechanism of active transport, which often occurs in living systems, is beyond the scope of this text. Active transport requires a certain amount of energy, as can be seen from the fact that live kidneys require an efficient oxygen supply. 

Distribution of penicillin antibiotics is limited to extracellular fluids, but inflammation may enhance their distribution into tissues. Penicillins are actively transported in kidney, brain, and liver. Most penicillins undergo minimal hepatic metabolism and are cleared from the plasma primarily by renal excretion. Secretion of penicillins by the renal tubules results in high urine concentrations and rapid elimination from the body (50). 

The half-life will be independent of the dose, provided that the elimination is first order and therefore should remain constant. Changes in the half-life, therefore, may indicate alteration of elimination processes due to toxic effects because the half-life of a compound reflects the ability of the animal to metabolize and excrete that compound. When this ability is impaired, for example, by saturation of enzymic or active transport processes, or if the liver or kidneys are damaged, the half-life may be prolonged. For example, after overdoses of paracetamol, the plasma half-life increases severalfold as the liver damage reduces the metabolic capacity, and in some cases, kidney damage may reduce excretion (see chap. 7). 

Mercury exists in three forms elemental, inorganic, and organic with different toxic effects. Elemental mercury is absorbed as a vapor and may enter the CNS and cause toxicity there. Inorganic mercury is poorly absorbed, but the cysteine conjugate of mercury is concentrated in the kidney by active transport. The kidney is the main target organ (also gastrointestinal tract if exposure by that route). 

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