Biotransformation, renal

Modes of drug elimination are biotransformation, renal excretion, and excretion by other routes (e.g., bile, sweat, lungs, etc.). Most drugs follow first-order elimination rates. Figures l-MOa and 1-1-lOb compare zero- and first-order elimination, and Figure 1-1-11 demonstrates how the t, and the theoretical zero time plasma concentration (C°) can be graphically determined. Two important relationships are dose = x C° and t, = 0.7/k (k = the first-order rate constant of elimination). 

HU, a freely water-soluble molecule, crosses the intestinal wall and other cells by passive diffusion [5, 6], and tissue concentration of HU rapidly matches its blood concentration [7]. The oral bioavailability of HU is nearly complete and hence therapeutically simple to administrate. HU undergoes biotransformation and is converted into urea by a yet-to-be identified hepatic P450 monooxygenase (CYP) enzyme [8, 9], Elimination of HU and its metabolites involves both renal and non-renal mechanisms. 

Biotransformation involves the chemical alteration of a molecule to alter its effects. This often terminates the pharmacological effects of a drug, but active metabolites are produced in some cases. Biotransformation also changes the ease with which a drug is eliminated. This involves conversion of the drug to a more hydrophilic metabolite that enhances renal excretion. Although this process pertains to most drugs, it probably... 

As mentioned above, bioavailability is the degree to which a drug reaches the intended site of action. The amount of drug that reaches systemic circulation will depend on the processes of absorption, distribution, and biotransformation (when the route of administration exposes the drug to first-pass metabolism). Pharmacokinetics are often linear and when they are nonlinear it is often due to a saturation of protein binding, metabolism, or active renal transport. 

Metabolic pathways of chloroform biotransformation are shown in Figure 2-3. Metabolism studies indicated that chloroform was, in part, exhaled from the lungs or was converted by oxidative dehydrochlorination of its carbon-hydrogen bond to form phosgene (Pohl et al. 1981 Stevens and Anders 1981). This reaction was mediated by cytochrome P-450 and was observed in the liver and kidneys (Ade et al. 1994 Branchfiower et al. 1984 Smith et al. 1984). In renal cortex microsomes of... 

Methoxyflurane is an extremely powerful inhalation anesthetic that is an excellent skeletal muscle relaxant. However, its use is somewhat limited by its relatively high solubility, which causes the patient to make a slow transition back into consciousness. Another disadvantage of methoxyflurane is that fluorine ions are the product of its biotransformation, which may lead to the development of renal failure. Therefore, it is recommended to use methoxyflurane for anesthesia during interventions of no more than 2 h. A very common synonym for methoxyflurane is penthrane. 

Hepatic 0-dealkylation and glucuronide formation appear to be major pathways of biotransformation. Only about 10% of orally administered prazosin is excreted in the urine. Plasma levels of prazosin are increased in patients with renal failure the nature of this interaction is unknown. 

Another concern associated with the use of enflurane is its biotransformation, which leads to increased plasma fluoride. Following lengthy procedures in healthy patients, fluoride may reach levels that result in a mild reduction in renal concentrating ability. Thus, enflurane should be used cautiously in patients with clinically significant renal disease. 

In the oral cavity, drug metabolism occurs in mucosal epithelial cells, microorganisms, and enzymes in the saliva metabolism also takes place in renal and hepatic tissue once the drug is swallowed. Although biotransformation of agents in the oral cavity is potentially an important aspect of reducing effective drug concentra-... 

Umeda, M., S. Amagaya, and Y. Ogihara. Effects of certain herbal medicines on the biotransformation of arachidonic acid A new pharmacological testing method using serum. J Ethnopharmacol 1988 23(1) 91-98. Nishio, S., S. Hayashi, and H. Yoshi-hara. The effects of ginseng and ginger combination and rhubarb licorice combination on patients with chronic renal failure. Int J Orient Med 1993 18(3) 148-155. 

Plasma protein binding generally limits renal tubular secretion and biotransformation... 

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. 

The oximes contain a quaternary ammonium group that contributes to their acidity and their strong binding to the inhibited enzyme. This appears to be a key structural element in known reactivators, but it tends to make them poorly soluble in lipids. Practically, this means that the drugs are slowly absorbed from the gastrointestinal tract, have difficulty entering the brain, do not easily enter hepatic cells to be biotransformed, and are not reabsorbed from the renal tubular urine. 

Small molecules are eliminated from the body largely by means of drug metabolism enzymes in the liver and other tissues and by urinary excretion. Large molecules are also eliminated by renal and hepatic mechanisms. Proteins that are less than 40 to 50 kDa are cleared by renal filtration with little or no tubular reabsorption. Larger proteins are less likely to be filtered but may be subject to phagocytosis in hepa-tocytes and Kupfer cells in the liver. Protein biotransformation—denaturation, proteolysis, and oxidative metabolism—is also important. 

Diseases that directly affect hepatic integrity include cirrhosis, viral infections, and collagen vascular diseases. Diseases that indirectly affect function include metabolic disorders (e.g., azotemia secondary to renal insufficiency) and cardiac disease. Although decreased left ventricular output can result in a decrease in hepatic arterial flow, right ventricular failure causes hepatic congestion, reducing the first-pass effect and delaying biotransformation. 

The potential for desflurane to cause renal or hepatic toxicity is small given its minimal biotransformation. Prolonged exposure does not cause an increase in plasma inorganic fluoride concentrations. 

Most metabolic biotransformations occur at some point between absorption of the drug into the general circulation and its renal elimination. A few transformations occur in the intestinal lumen or intestinal wall. In general, all of these reactions can be assigned to one of two major categories called phase I and phase II reactions (Figure 4-1). 

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