Excretion pump

ATP-dependent process, aided by the bile-salt excretion pump (BSEP) expression in the canalicular membrane. Conjugation increases the aqueous solubility of the bile adds, and renders these bile adds largely impermeable to the cell membranes of the intestine and duodenum hence, they are unable to leave the intestinal lumen. This allows bile-add levels to rise in the lumen, ultimately reaching sufficient concentrations to form micelles, which allow lipid emulsification and subsequent absorption. 

An essential requirement for diffusion of Na+ ions is the creation of a concentration gradient for sodium between the filtrate and intracellular fluid of the epithelial cells. This is accomplished by the active transport ofNa+ ions through the basolateral membrane of the epithelial cells (see Figure 19.4). Sodium is moved across this basolateral membrane and into the interstitial fluid surrounding the tubule by the Na+, K+-ATPase pump. As a result, the concentration of Na+ ions within the epithelial cells is reduced, facilitating the diffusion of Na+ ions into the cells across the luminal membrane. Potassium ions transported into the epithelial cells as a result of this pump diffuse back into the interstitial fluid (proximal tubule and Loop of Henle) or into the tubular lumen for excretion in the urine (distal tubule and collecting duct). 

Potassium ion secretion. Potassium ions are secreted in the distal tubule and the collecting duct. These ions diffuse down their concentration gradient from the peritubular capillaries into the interstitial fluid. They are then actively transported up their concentration gradient into the tubular epithelial cells by way of the Na+, K+ pump in the basolateral membrane. Finally, potassium ions exit the epithelial cells by passive diffusion through K+ channels in the luminal membrane and enter tubular fluid to be excreted in the urine. 

Bile salt export pump (BSEP gene symbol ABCB11) mediates the biliary excretion of nonconjugated bile salts, such as taurocholic acid, glycocholic acid and cholic acid, and therefore is responsible for the formation of the bile acid-dependent bile flow [97, 98]. Its hereditary defect results in the acquisition of PFIC2, a potentially lethal disease which requires liver transplantation [17, 81, 82, 99]. As discussed in Section 12.5.2, the inhibition of BSEP following drug administration may result in cholestasis. 

Bolder U, Trang NV, Hagey LR, Schteingart CD, Ton-Nu HT, Cerre C et al. Sulindac is excreted into bile by a canalicular bile salt pump and undergoes a cholehepatic circulation in rats. Gastroenterology 1999 117(4) 962—971. 

Intracellular thiolate ligands such as glutathione (GSH, the tripeptide y-L-Glu-L-Cys-Gly) are believed to inactivate cisplatin because the reactions with cisplatin tend to be irreversible (35). Elevated levels of GSH have been observed in cisplatin-resistant cells. Recently, it has been shown that an MRP gene, which encodes a human ATP-dependent glutathione S-conjugate export pump (GS-X pump), is expressed at higher levels in cisplatin-resistant (HL-60/R-CP) cells than in sensitive cells (36). The GS-X pump may contribute to the excretion of Pt-GS complexes from cells (37). 

Figure 15.2 Transport proteins involved in the intestinal absorption and the renal and hepatic excretion of drugs. In the intestine, drugs are taken up from the luminal side into enterocytes before the subsequent elimination into blood. In hepatocytes, drugs are taken up from the blood over the basolateral membrane and excreted over the canalicular membrane into bile. In the renal epithelium, drugs undergo secretion (drugs are taken up from the blood and excreted into the urine) or reabsorption (drugs are taken up from the urine and are excreted back into blood). Uptake transporters belonging to the SLC transporter superfamily are shown in red and export pumps...

In addition to its pump function, the heart is also a secretory organ. Cardiac cells produce two small peptides, the natriuretic factors, which oppose the vasoconstrictive actions of noradrenaline (norepinephrine) from the sympathetic nervous system and of the peptide angiotensin II. By causing vasodilation and natriuresis (increased excretion of sodium in the urine), atrial natriuretic peptide (ANP) secreted from the atria and B-type natriuretic peptide (BNP) secreted by both atria and probably more significantly, from the ventricles, reduce blood pressure. The stimulus to secretion of natriuretic peptides is wall stretch of the chambers of the heart, indicating volume and pressure overload of the vascular system. A third member of the natriuretic peptide family, CNP, is secreted by endothelial cells. 

The second thing that happens is a very good thing. The liver upregulates its LDL receptor level. In snm, the liver does the two things that it can do to maintain an adequate source of its cholesterol pump up the synthesis (to normal or slightly subnormal rates only) and pnmp np the seqnestration of cholesterol from the blood LDLs. The net effect is that the rate of excretion of cholesterol from the body is increased due to the increase in the nnmber of LDL receptors expressed on hepatic cells without compromising the availability of cholesterol to meet cellular needs. 

Active transporters are thought to play an important role in the pharmacokinetics of drugs, not only because they can regulate the permeability of drugs as substrate-specific efflux or influx pumps, but also because of their widespread presence across in vivo membrane systems, from the intestinal epithelia to the BBB. Generally speaking, the absorption direction transporters tend to have narrower substrate specificity than the excretion direction transporters. Active transporters also play a significant role in biliary and renal excretion. 

Since approximately 130 mL of plasma water is filtered across the porous glomerular capillary membranes each minute (190 L/day), the kidney is admirably suited for its role in drug excretion. As the ultrafiltrate is formed, any drug that is free in the plasma water, that is, not bound to plasma proteins or the formed elements in the blood (e.g., red blood cells), will be filtered as a result of the driving force provided by cardiac pumping. 

While there seems to be little in common between intractable epilepsy and cancer, researchers in each field have focused on a common mechanism underlying multidrug resistance a cellular pump called P-glycoprotein (Pgp). Pgp protects cells from toxic substances by actively excreting the toxic agent. The pumps reside in tissues that are extensively exposed to toxic material liver, lungs, kidney, intestine, placenta, and blood-brain barrier. How-... 

Figure 12.6 Mechanism of action of mineralocortjcoid receptor antagonists in the collecting tubule. Aldosterone enters the tubular cell by the basolateral surface and binds to a specific mineralocorticoid receptor (MNR) in the cytoplasm. The hormone receptor complex triggers the production of an aldosterone-induced protein (AlP) by the cell nucleus (NUC). The AIP acts on the sodium ion channel (ic) to augment the transport of Na+across the basolateral membrane and in to the cell. An increase in AIP activity leads to the recruitment of dormant sodium ion channels and Na pumps (P) in the cell membrane. AIP also leads to the synthesis of new channels and pumps within the cell. The increase in Na+conductance causes electrical changes in the luminal membrane that favour the excretion of intracellular cations, such as K+and H-h. Spironolactone competes with aldosterone for the binding site on the MNR and forms a complex which does not excite the production of AIP by the nucleus.

It is about an active mechanism depending on the Na+-K+-ATPase enzyme located in the lateral plasma membrane of the endothelial cells. It enables the penetration of potassium into the cell against the excretion of sodium into the aqueous humor. Then this latter becomes hypertonic in comparison with the stroma and thus drains the water. In normal conditions, the pump can adapt to the physiological needs. Actually, the moves of the sodium ion are relative to those of the bicarbonate ion (responsible for the negative polarization of the back side of the endothelial cell) and to the pH variation. And yet, the bicarbonate comes from the aqueous humor and from the intracellular transformation of carbon dioxide and water by carbonic anhydrase. All of this shows the good functioning of the pumps depends on the integrity of the plasma... 

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