Excretion transporters

Respiration—transport of oxygen from the lungs to the tissues and of COj from the tissues to the lungs Nutrition—transport of absorbed food materials Excretion—transport of metabolic waste to the kidneys, lungs, skin, and intestines for removal Maintenance of the normal acid-base balance in the body... 

Certain cyclic dipeptides have the ability to be transported by additional paracellular mechanisms, thereby enhancing their transport. " Not only absorptive transport but also excretive transport are observed for certain cyclic dipeptides. The intestinal absorption of certain cyclic dipeptides consists of carrier-mediated absorptive... 

PK modeling can take the form of relatively simple models that treat the body as one or two compartments. The compartments have no precise physiologic meaning but provide sites into which a chemical can be distributed and from which a chemical can be excreted. Transport rates into (absorption and redistribution) and out of (excretion) these compartments can simulate the buildup of chemical concentration, achievement of a steady state (uptake and elimination rates are balanced), and washout of a chemical from tissues. The one- and two-compartment models typically use first-order linear rate constants for chemical disposition. That means that such processes as absorption, hepatic metabolism, and renal excretion are assumed to be directly related to chemical concentration without the possibility of saturation. Such models constitute the classical approach to PK analysis of therapeutic drugs (Dvorchik and Vesell 1976) and have also been used in selected cases for environmental chemicals (such as hydrazine, dioxins and methyl mercury) (Stem 1997 Lorber and Phillips 2002). As described below, these models can be used to relate biomonitoring results to exposure dose under some circumstances. 

Molecular size can be a further limiting factor in oral absorption [51]. The Lipinski s rule-of-5 proposes an upper limit of MW 500 as acceptable for orally absorbed compounds [136]. High molecular weight (MW) compounds tend to undergo biliary excretion. High MW is a necessary but not sufficient condition for biliary excretion. Substrates of the excretion transporters must also be anionic, that is, resemble the natural substrates, which are biliary acids. Size and shape parameters are generally not measured but rather calculated. A measured property is the so-called cross-sectional area, which is obtained from surface activity measurements [52]. 

The amount of each element required in daily dietary intake varies with the individual bioavailabihty of the mineral nutrient. BioavailabiUty depends both on body need as deterrnined by absorption and excretion patterns of the element and by general solubiUty, and on the absence of substances that may cause formation of iasoluble products, eg, calcium phosphate, Ca2(P0 2- some cases, additional requirements exist either for transport of substances or for uptake or binding. For example, calcium-binding proteias are iavolved ia calcium transport an intrinsic factor is needed for vitamin cobalt,... 

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). 

Absorption, Transport, and Excretion. The vitamin is absorbed through the mouth, the stomach, and predominantly through the distal portion of the small intestine, and hence, penetrates into the bloodstream. Ascorbic acid is widely distributed to the cells of the body and is mainly present in the white blood cells (leukocytes). The ascorbic acid concentration in these cells is about 150 times its concentration in the plasma (150,151). Dehydroascorbic acid is the main form in the red blood cells (erythrocytes). White blood cells are involved in the destmction of bacteria. 

Hydroxy vitamin D pools ia the blood and is transported on DBF to the kidney, where further hydroxylation takes place at C-1 or C-24 ia response to calcium levels. l-Hydroxylation occurs primarily ia the kidney mitochondria and is cataly2ed by a mixed-function monooxygenase with a specific cytochrome P-450 (52,179,180). 1 a- and 24-Hydroxylation of 25-hydroxycholecalciferol has also been shown to take place ia the placenta of pregnant mammals and ia bone cells, as well as ia the epidermis. Low phosphate levels also stimulate 1,25-dihydtoxycholecalciferol production, which ia turn stimulates intestinal calcium as well as phosphoms absorption. It also mobilizes these minerals from bone and decreases their kidney excretion. Together with PTH, calcitriol also stimulates renal reabsorption of the calcium and phosphoms by the proximal tubules (51,141,181—183). 

Enzymes. Invertase (P-fmctofuranosidase) is commercially produced from S. cerevisiae or S. uvarum. The enzyme, a glycoproteia, is not excreted but transported to the cell wall. It is, therefore, isolated by subjecting the cells to autolysis followed by filtration and precipitation with either ethanol or isopropanol. The commercial product is available dry or ia the form of a solutioa containing 50% glycerol as a stabilizer. The maia uses are ia sucrose hydrolysis ia high-test molasses and ia the productioa of cream-ceatered candies. 

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). 

Lungs also secrete nonvolatile compounds. Lipid-soluble compounds may thus be transported with the alveobronchotracheal mucus to the pharynx, where they are swallowed. They may then be excreted or reabsorbed. Particles are also removed by this mucociliary escalator. 

The co-administration of drugs which inhibit the transporters involved in renal tubular secretion can reduce the urinaty excretion of drugs which are substrates of the transporter, leading to elevated plasma concentrations of the drugs. For example, probenecid increases the plasma concentration and the duration of effect of penicillin by inhibiting its renal tubular secretion. It also elevates the plasma concentration of methotrexate by the same mechanism, provoking its toxic effects. 

Gall bladder Various oral cystographic agents, e.g., iopanoic acid Telepaque etc. Anion transport Urich K, Speck U (1991) Biliary excretion of contrast media. Progr Pharmacol Clin Pharmacol 8 307-322... 

Bile ducts Various intravenous cholegraphic agents, e.g., iodipamide Biligrafin Anion transport Lin SK et al (1977) Iodipamide kinetics Capacity-limited biliary excretion with simultaneous pseudo-first-order renal excretion. J Pharm Sci 66 1670-1674... 

Many of the phase 1 enzymes are located in hydrophobic membrane environments. In vertebrates, they are particularly associated with the endoplasmic reticulum of the liver, in keeping with their role in detoxication. Lipophilic xenobiotics are moved to the liver after absorption from the gut, notably in the hepatic portal system of mammals. Once absorbed into hepatocytes, they will diffuse, or be transported, to the hydrophobic endoplasmic reticulum. Within the endoplasmic reticulum, enzymes convert them to more polar metabolites, which tend to diffuse out of the membrane and into the cytosol. Either in the membrane, or more extensively in the cytosol, conjugases convert them into water-soluble conjugates that are ready for excretion. Phase 1 enzymes are located mainly in the endoplasmic reticulum, and phase 2 enzymes mainly in the cytosol. 

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. 

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