Liver metabolic functions

The kidneys are located on the posterior part of the abdomen on either side of the spine, below the diaphragm, and behind the liver and stomach. They are bean-shaped and weigh approximately 150 grams (0.33 lb) each. The primary function of the kidneys is excretion. They work to excrete waste products through a series of steps involving glomerular filtration, secretion, and reabsorption. The kidneys also have several endocrine (e.g., production of erythropoietin and renin) and metabolic (e.g., vitamin D activation and drug metabolism) functions. 

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

No one tissue can survive metabolically without the others. Each of the four major tissue types (liver, muscle, adipose, brain) has a specialized metabolic function. There are some differences in the metabolic pathways in each tissue however, these differences are relatively simple and serve to specialize the metabolic functions of the different tissue types. There is real cooperation between the different organs. Each organ has its own metabolic profile, its own needs, and its own capabilities. 

Rapidly metabolize PAHs by liver mixed-function oxidases, with little evidence of accumulation... 

Robinson KM, Yarbrough JD. 1978b. A study of mirex induced changes in liver metabolism and function with emphasis on liver enlargement. Fed Proc, Fed Am Soc Exp Biol 37 699. 

Liver cells contain two different but closely related enzymes glycerol phosphate dehydrogenase which is specific for NAD, and acylglycerol phosphate dehydrogenase, which is NADP specific. Both enzymes have B stereospecificity for the pyridine nucleotide 93. They apparently have different metabolic functions. 

Hepatocytes make up 60-70% of the total number of liver cells. They have a well-organized intracellular structure with huge numbers of cell organelles to maintain the high metabolic profile. At the apical side or canalicular membrane the cell is specialized for the secretion of bile components. There are several ATP-dependent transport carriers located on this side of the membrane, which transport bile salts, lipids and xenobiotics into the canaliculus. On the sinusoidal side, the cells specialize in uptake and secretion of a wide variety of components. To increase the surface of the membrane for this exchange with the bloodstream, the sinusoidal domain of the membrane is equipped with irregular microvilli. The microvilli are embedded into the fluid and matrix components of the space of Disse and are in close contact with the sinusoidal blood because of the discontinuous and fenestrated SECs. To facilitate its metabolic functions numerous membrane transport mechanisms and receptors are situated in the membrane. 

Because these different viability tests all reflect different aspects of cell viability, the choice of test depends on the aim of the study. For toxicity studies where biotransformation is an important bioactivation or detoxification step, metabolic function tests should be included to judge the validity of the method, whereas viability tests are needed to assess toxic effects. Both positive and negative controls should be included in such studies. When human liver is used, the characterization of metabolic activity is especially important because of the large inter-individual variability associated with this property [75]. 

Cyanocoba/am/n- Cyanocobalamin is rapidly absorbed from IM and subcutaneous injection sites the plasma level peaks within 1 hour. Once absorbed, it is bound to plasma proteins, stored mainly in the liver and is slowly released when needed to carry out normal cellular metabolic functions. Within 48 hours after injection of 100 to 1,000 meg of vitamin B-12, 50% to 98%... 

These dosage recommendations are extremely important because blood concentration in all premature and full-term infants younger than 2 weeks of age differs from that of other infants because of variations in the maturity of the metabolic functions of the liver and kidneys. 

Thus, the accumulation of vitamins respectively micronutrients in single tissues is not limited to a pure storage process like the storage of vitamin A in the liver, but is often connected with important and tissue-specific metabolic functions. 

Incompletely absorbed from the GI tract. Protein binding 6% 16%. Minimal liver metabolism. Primarily excreted unchanged in urine. Removed by hemodialysis. Half-life 6-7 hr (increased in impaired renal function). 

Mechanism of Action Acts as a coenzyme for various metabolic functions, including fat and carbohydrate metabolism and protein synthesis. Therapeutic Effect Necessary for cell growth and replication, hematopoiesis, and myelin synthesis. Pharmacokinetics In the presence of calcium, absorbed systemically in lower half of ileum. Initially, bound to intrinsicfactor this complex passes down intestine, binding to receptor sites on ileal mucosa. Protein binding High, Metabolized in the liver. Primarily eliminated unchanged in urine. Half-life 6 days. 

These hormones also have profound effects on the function of the liver. Some of these effects are deleterious and will be considered below in the section on adverse effects. The effects on serum proteins result from the effects of the estrogens on the synthesis of the various 2 globulins and fibrinogen. Serum haptoglobins produced in the liver are depressed rather than increased by estrogen. Some of the effects on carbohydrate and lipid metabolism are probably influenced by changes in liver metabolism (see below). 

The liver is involved in a variety of both synthetic and catabolic functions, including metabolism of amino acids, lipids, carbohydrates, protein synthesis and detoxification [ 1 ]. These metabolic functions are performed mainly by hepatocytes, although the liver is made of three major cell types (hepatocytes, biliary epithelial cells and Kupffer cells). Exerting many different metabolic functions, the liver contains several different and specific enzymes, leakage of which into the bloodstream occurs in hepatic diseases. 

Extracorporeal devices to support a compromised liver were reviewed by Allen et al. and Strain and Neubcrgcr.Various nonbiological approaches such as hemodialysis or hemoperfusion over charcoal have met with limited success, presumably because these systems inadequately replaced the synthetic and metabolic functions of the liver. Conversely, biological approaches such as hollow fiber devices, flat plate systems, perfusion beds, and suspension reactors have shown encouraging results but are difficult to implement in a clinical setting. 

Cutaneous biotransformation is mostly associated with the stratum basale layer where there can be phase I and phase II metabolism. However, the skin is not very efficient, compared to the liver. The epidermal layer accounts for the major portion of biochemical transformations in skin, although the total skin activity is low (2-6% that of the liver). Where activity is based on epidermis alone, that layer is as active as the liver or, in the case of certain toxicants, several times more active. For some chemicals, metabolism can influence absorption, and transdermal delivery systems of drugs utilize this activity. For example prodrug such as lipid esters are applied topically, and cutaneous esterases liberate the free drug. These basal cells and extracellular esterases have been shown to be involved in detoxification of several pesticides and bioactivation of carcinogens such as benzo(a)pyrene. For rapidly penetrating substances, metabolism by the skin is not presently considered to be of major significance, but skin may have an important first-pass metabolic function, especially for compounds that are absorbed slowly. 

Several interesting and representative trends are apparent in the data of Table 8.2. In terms of age, infants tend to have poorly developed metabolic function, but children have very high metabolic rates. Metabolism slows in adulthood and continues to decrease in geriatric patients. With regard to health problems, impaired liver function has the most dramatic effect on the half-life of theophylline relative to all the listed conditions. The impact of pregnancy is... 

Toxic effects to the liver are studied under the topic of hepatotoxicity, and substances that are toxic to the liver are called hepatotoxins. Much is known about hepatotoxicity from the many cases of liver toxicity that are a manifestation of chronic alcoholism.6 Liver injury from excessive alcohol ingestion initially hampers the ability of the organ to remove lipids, resulting in their accumulation in the liver (fatty liver). The liver eventually loses its ability to perform its metabolic functions and accumulates scar tissue, a condition known as cirrhosis. Inability to synthesize clotting factors can cause fatal hemorrhage in the liver. 

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