Kidneys, elimination processes

The pharmacokinetic term clearance (CT) best describes the efficiency of the elimination process. Clearance by an elimination organ (e.g., liver, kidney) is defined as the volume of blood, serum, or plasma that is totally cleared of drug per unit time. This term is additive the total body or systemic clearance of a drug is equal to the sum of the clearances by individual eliminating organs. Usually this is represented as the sum of renal and hepatic clearances CT = CT renal -I- CL hepatic. Clearance is constant and independent of serum concentration for drugs that are eliminated by first-order processes, and therefore may be considered proportionally constant between the rate of drug elimination and serum concentration. 

When a single dose of radiolabeled sulfadiazine was administered to eels at 7 C (200), highest initial radioactivity was observed in blood, liver, kidney, and skin, with a tendency for accumulation in bile and skin. In another pharmacokinetic study (201) on sea-water rainbow trout fed a combination of sulfadia-zine-trimetlroprim, the elimination process for both sulfadiazine and trimethoprim rapidly reached a point at which only a small but persistent residue was left at 8 C as opposed to 10 C, sulfadiazine was the more potent residue promoter, still being detected at 90 days posttreatment. This was suggested to be a result of the greater binding ability of sulfadiazine as a weak electrolyte. The authors proposed a witlidrawal period for sulfadiazine-trimethoprim of 60 days at water temperatures above 10 C for tabled-size fish, and a prohibition on its use below 10 C for such fish. 

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). 

Moreover, combinations of these models can also be used to roughly describe physiological considerations. For instance, if the drug is metabolized by the liver and simultaneously eliminated by the kidney, a gamma profile is obtained as solution of (7.3), where the a/t term expresses the structural heterogeneity of the liver, and the term j3, the homogeneous elimination process from the kidney. 

Sarin and its corresponding nontoxic hydrolysis products (IMPA, and additional methyl phosphonic acids) are predominantly eliminated via the kidneys which are thus more important for detoxification than the liver (Little et al, 1986 Waser and Streichenberg, 1988). Urinary excretion happens quite rapidly as demonstrated for single dose s.c. application of sarin, cyclosarin, and soman to rats (Shih et al, 1994). The terminal elimination half-life was found to be 3.7 =E 0.1 h for sarin and 9.9 0.8 h for cyclosarin. In contrast soman showed a biphasic elimination with terminal half-fives of about 18.5 h and 3.6 h (Shih et al, 1994). Maximum peak levels of sarin metabolites in urine were detected 10-18 h after exposure (Minami et al, 1997) and after 2 days hydrolyzed sarin metabolites had been excreted nearly quantitatively (Shih et al, 1994). In contrast, even at 5 days post-exposure soman metabolite recovery was only 62% (Shih et al, 1994). Excretion of soman from blood, fiver, and kidney compartments following cfiemical and enzymatic hydrolysis is considered a first-order elimination process (Sweeney et al, 2006). 

Medications metabolized by the liver are secreted into bile. Bile enters the intestine and is eliminated in feces. Fat-soluble medications are reabsorbed from bile into the bloodstream and returned to the liver to be metabolized and eliminated by the kidneys. This process is called the enterohepatic cycle. Medications that are not metabolized by the liver are eliminated by the lungs at a rate that corresponds to the patient s respiration rate. These are volatile medications, such as anesthetics and medications that are metabolized to C02 and H20. Side effects such as rashes and skin reaction are commonly seen at sweat and salivary glands. For example, a patient may report tasting the medication. Medication excreted into saliva is eventually swallowed, reabsorbed, and... 

Liver or kidney deficiency increases the risk of toxicity, as the normal detoxification and elimination processes will not be functioning properly (see Chapter 28). 

Excretion factors are often related to lipophilicity. More lipophilic compounds tend to be excreted by the Hver into the bile, resulting in elimination ultimately in the feces. As this is a relatively slow process, much of the radioactivity having a shorter half-life decays before being eliminated. Polar compounds are more likely to be excreted by the kidneys. 

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). 

The toxic effect depends both on lipid and blood solubility. I his will be illustrated with an example of anesthetic gases. The solubility of dinitrous oxide (N2O) in blood is very small therefore, it very quickly saturates in the blood, and its effect on the central nervous system is quick, but because N,0 is not highly lipid soluble, it does not cause deep anesthesia. Halothane and diethyl ether, in contrast, are very lipid soluble, and their solubility in the blood is also high. Thus, their saturation in the blood takes place slowly. For the same reason, the increase of tissue concentration is a slow process. On the other hand, the depression of the central nervous system may become deep, and may even cause death. During the elimination phase, the same processes occur in reverse order. N2O is rapidly eliminated whereas the elimination of halothane and diethyl ether is slow. In addition, only a small part of halothane and diethyl ether are eliminated via the lungs. They require first biotransformation and then elimination of the metabolites through the kidneys into the... 

Following oral administration, the intestinal absorption of Li+ occurs primarily in the small intestine and the subsequent movement of Li+ into the blood stream is a passive process, via a paracellular route, with very little Li+ accumulating in the intestinal cells [51,52]. The excretion of Li+ is almost entirely by the kidneys with only very small amounts (<1%) being excreted in the feces, sputum, sperm, and sweat. The elimination half-life of Li+ is approximately 20-30 hours. 

The elimination rate of a compound (directly or by biotransformation) from an organism determines the extent of the bioconcentration and depends both on the chemical and the organism. Direct elimination includes transport across the skin or respiratory surfaces, secretion in gall bladder bile, and excretion from the kidney in urine. Other processes are moulting (for arthropods), egg deposition (fish, invertebrates) and transfer to offspring or via lactation (in mammals), which are more specific and not usually contemplated in bioconcentration determination. 

Polarized tissues directly involved in drug absorption (intestine) or excretion (liver and kidney) and restricted drug disposition (blood-tissue barriers) asymmetrically express a variety of different drug transporters in the apical or basolateral membrane resulting in vectorial dmg transport. This vectorial dmg transport is characterized by two transport processes the uptake into the cell and subsequently the directed elimination out of the cell (Figure 15.3). Because the uptake of substances... 

Elimination takes place largely by way of the kidney, which acts like an active filter for all unwanted body substances, although sometimes it gets damaged in the process as we have already noted. Some elimination of ingested material that has not been absorbed also takes place by way of the bowel, or even, in the case of volatile materials such as alcohol, by... 

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