Kidneys biotransformation/excretion

Acetylated MS-222 was found in much higher concentrations in the urine than in the blood of rainbow trout. This suggests that the kidney concentrated the drug metabolite, or that MS-222 was acetylated in the kidney and excreted in the urine (28). Weber (31) stated that acetylation of p-aminobenzoic acid and sulfamethazine is catalyzed by most of the tissues in the body. He showed that in rabbits the acetylation of these amines by the kidney of rabbit is a small percentage of the total acetylation capability, but that the kidney is involved in this biotransformation. 

Relative to toxicology, the basic function of metabolism is to increase the rate of elimination of foreign chemicals (i.e., xenobiotics). The same factors that allow xenobiotics to be absorbed (e.g., fat-soluble) also greatly reduce their elimination from the body. As a result, we would quickly be overwhelmed by absorbed xenobiotics. Metabolism involves a process of biotransformation in which the chemical structure of the xenobiotic is changed. This change increases the water solubility of the chemical, which reduces the ability of the chemical to be stored in the fat, increases its rate of filtration by the kidneys (see excretion, below), and thereby greatly increases the rate of elimination for the chemical. This function keeps us from being overwhelmed by exposure to unwanted chemicals. 

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 terminator of drug action is, of course, elimination. Elimination is a composite of excretion (kidney, etc.) and biotransformation (metabolism). The primary measure of drug elimination from the whole body is clearance, CLt, defined as the volume of plasma fluid removed of drug per unit time. It is a direct measure of the loss of the drug from the system and can be calculated from Eq. (3.5) after IV administration of a dose of the drug. 

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. 

Dexrazoxane was also hydrolyzed enzymatically in the liver and kidney by dihydropyrimidine aminohydrolase. This enzyme could hydrolyze one but not a second ring of this molecule. Levrazoxane, the enantiomer of dexrazoxane, was also hydrolyzed enzymatically by DHPase in liver homogenates, but at a rate 4.5-fold slower [136], However, in vivo studies in rats dosed with razoxane (the racemic mixture of levrazoxane and dexrazoxane) revealed only a relatively small difference in elimination of the two enantiomers. This suggests that distribution and excretion reduced the impact of stereoselective biotransformation on the pharmacokinetics of these two enantiomers [137]. 

Rabbits form bicarbonate in the gut and absorb it. They do not have to form new bicarbonate in the kidneys and need not excrete ammonium ions in the urine, but they still need to excrete organic anions. These organic anions are accompanied in the urine by sodium or potassium ions, which can generate a severe negative sodium balance for the period that the rabbits are on a browse diet(Iason and Palo, 1991). Therefore, lagomorphs excrete biotransformational... 

The most significant metabolite of letrozole (3) is its secondary alcohol metabolite (SAM) 23 (Scheme 3.4). Biotransformation of letrozole is the main elimination mechanism, with the glucuronide conjugate of the secondary alcohol metabolite (24) being the prominent species found in urine. However, the total body clearance of letrozole is slow (2.21 L/h). Its elimination half-life is long, at 42 h. Letrozole and its metabolites are excreted mainly via the kidneys. 

Ethylene glycol, an industrial solvent and an antifreeze compound, is involved in accidental and intentional poisonings. This compound is initially oxidized by alcohol dehydrogenase and then further biotransformed to oxalic acid and other products. Oxalate crystals are found in various tissues of the body and are excreted by the kidney. Deposition of oxalate crystals in the kidney causes renal toxicity. Ethylene glycol is also a CNS depressant. In cases of ethylene glycol poisoning, ethanol is administered to reduce the first step in the biotransformation of ethylene glycol and, thereby, prevent the formation of oxalate and other products. 

Dimercaprol is FDA-approved as single-agent treatment of acute poisoning by arsenic and inorganic mercury and for the treatment of severe lead poisoning when used in conjunction with edetate calcium disodium (EDTA see below). Although studies of its metabolism in humans are limited, intramuscularly administered dimercaprol appears to be readily absorbed, metabolized, and excreted by the kidney within 4-8 hours. Animal models indicate that it may also undergo biliary excretion, but the role of this excretory route in humans and other details of its biotransformation are uncertain. 

Once a drug is biotransformed, it has to be eliminated from the body. Although the main exit is through the kidneys, materials can also be excreted in the feces and through sweat, tears and milk. Some molecules are not easily converted from lipophilic to hydrophilic and so are reabsorbed, eventually finding their way into the bile and large intestine. In fact, there are transport systems which will actually secrete some drugs into the bile. 

Some drugs are eliminated from the body unchanged, but most drugs undergo biotransformation. Biotransformation enables a drug to be converted to forms readily excreted by the liver and kidney, whereas sometimes it enables a drug to be converted to an active form. These conversions almost always result in metabolites that are more polar than the parent drug. 

Regardless of the type of chemical reaction used, biotransformation also helps in metabolite excretion from the body by creating a more polar compound.18,53 60 After one or more of the reactions just described occurs, the remaining drug metabolite usually has a greater tendency to be ionized in the body s fluids. The ionized metabolite is more water soluble, thus becoming transported more easily in the bloodstream to the kidneys. Upon reaching the kidneys, the polar metabolite can be excreted from the body in the urine. The contribution of biotransformation toward renal excretion is discussed in a later section. 

Absorption of a mycotoxin will occur when it crosses body membranes and enters the blood stream. The primary sites of mycotoxin absorption are the gastrointestinal tract (ingestion of contaminated food), lungs (inhalation of contaminated particles or toxin-containing fungal spores) and the skin (direct contact with contaminated materials or pure mycotoxins). When the mycotoxin enters the blood it is then available for distribution. Livers and kidneys have a high capacity to bind many mycotoxins while other mycotoxins are highly lipophilic and can concentrate in body fat. In the final outcome a toxic response by a mycotoxin will be critically influenced by the rate of absorption, distribution, biotransformation and excretion (Smith et al., 1994). 

This biotransformation is common to many xenobiotics and diminishes the potential toxicity of the substrate and facilitates its biliary and urinary elimination by increasing its hydrophilicity. Flavonoid metabolites are transported to extrahe-patic tissues and eventually to the kidneys, where they are excreted in the urine or incorporated into bile and excreted in feces.13 Because phase II metabolism is highly efficient with respect to the flavonoids, aglycones (except for anthocyanins)... 

Mammalian metabolism itself involves biotransformations of (generally hydrophobic) drugs in liver cells, kidney, and other organs to more polar, hydrophilic derivatives in order to allow excretion from the body. This process involves two types of reactions, classified as Phase I (functionalization) and Phase II (conjugation). This has been intensively reviewed and is covered by standard textbooks in pharmacology and pharmacy. 

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