Bile, excretion

Drug absorption is highly variable in neonates and infants [21,22]. Older children appear to have absorption patterns similar to adults unless chronic illness or surgical procedures alter absorption. Differences in bile excretion, bowel length, and surface area probably contribute to the reduced bioavailability of cyclosporine seen in pediatric liver transplant patients [22a]. Impaired absorption has also been observed in severely malnourished children [22b]. A rapid GI transit time may contribute to the malabsorption of carbamazepine tablets, which has been reported in a child [23]. Selection of a more readily available bioavailable dosage form, such as chewable tablets or liquids, should be promoted for pediatric patients. 

Leipold RJ (1995) Description and Simulation of a Tubular, Plug Flow Model to Predict the Effect of Bile Sequetrants on Human Bile Excretion. J Pharm Sci 84 pp 670-672. 

Many drugs that are taken up and metabolized by hepatocytes are excreted via the bile canahcuh into the bile. One of the remaining topics in liver slice research is the question of whether liver shces are capable of bile excretion via the bile canaliculus. Thompson et aZ.[93] showed that shces are capable of excreting bile acids, however, there is a need for more experiments to determine whether this excretion takes place across the bile canalicular membrane. 

Many companies have tried to develop peptidic renin inhibitors. Unfortunately these are rather large molecules and not unexpectedly poor absorption was often observed. The role of physicochemical properties has been discussed for this class of compounds. One of the conclusions was that compounds with higher lipophilicity were better absorbed from the intestine [29]. Absorption and bile elimination rate are both MW-dependent. Lower MW results in better absorption and less bile excretion. The combined influence of molecular size and lipophilicity on absorption of a series of renin inhibitors can be seen from Figure 1.7. The observed iso-size curves are believed to be part of a general sigmoidal relationship between permeability and lipophilicity [30-31] (for further details see Chapter 3). 

Bile excretion was >0. 1% of the aluminum load. When aluminum was administered via the external jugular vein, aluminum excretion was found to occur in the distal tubule of the kidney in pigs (Monteagudo et al. 1988). Yokel and McNamara (1985) did not find any age-related differences in the systemic clearance or half-time of aluminum in rabbits following parenteral administration of aluminum lactate. 

Dipyridamole is completely absorbed from the gastrointestinal tract, with peak plasma concentration occurring about 75 min after oral administration. Dipyridamole is highly bound to plasma proteins. A terminal half-life of 10-12 h has been reported. Dipyridamole is metabolized in the liver, and is mainly excreted as glucuronide conjugates in the bile. Excretion may be delayed by enterohepatic recirculation. A small amount is excreted in urine [2, 5, 85, 86]. 

Nimodipine is excreted in feces via the bile duct, and in urine via the glomular filtration, as metabolites [1, 10]. Fecal excretion is the major excretory route (greater than 67%) [11], The parent compound and its metabolites were detected in breast milk [9]. The average elimination half-life for the drug is reported to be 9 h, but the initial decline in plasma is much more rapid, equivalent to a half-life of 12 h [1], An average of 43% of bile-excreted nimodipine is subject to pronounced enterohepatic... 

CRITICAL ASSESSEMENT OF THE METHOD The method has the clear advantage of simplicity but does not measure the true bile excretion since the outflow from the bile bladder during the test period is neglected. 

A rough estimation whether anesthesia might relevantly misrepresent the situation of an awake animal should be performed comparing the bile excretion with the excretion via feces from the mass balance study (see example), the urine excretion or the radioactivity concentration in blood (so the bile fistula study should be extended to collect also body fluids such as terminal blood or the urine during the anesthesia). 

Poor vitamin D absorption, due to impaired bile excretion, leading to the development of osteoporosis. Poor vitamin K absorption leads to a tendency to bleed easily (lack of clotting factors) an enlarged spleen will reduce platelet numbers in the blood, exasperating this tendency. Bleeding into the gastrointestinal tract will result in anaemia. 

Disposition in the Body. Readily and almost completely absorbed after oral administration. More than 60% of a dose is excreted in the urine in 24 hours, including about 9% of the dose as the 2-hydroxy metabolite, 2-[4-(2-hydroxy-2-methylpropyl)phenyl]-propionic acid, about 17% as the conjugated hydroxy metabolite, about 16% as the 2-carboxy metabolite, 2-[4-(carboxypro-pyOphenyljpropionic acid, and about 19% as the conjugated carboxy metabolite (both metabolites are inactive) less than 10% of a dose is excreted unchanged. The remainder of the dose is probably eliminated in the faeces after excretion in the bile excretion is virtually complete within 24 hours. 

To overcome the pharmacokinetic problems of CSA, a microemulsion formulation was developed. Both forms are available commercially in the United States, referred to as cyclosporine, USP and cyclosporine, USP [MODIFIED]. The two formulations are not bioequivalent and should not be used interchangeably. The microemulsion formulation is self-emulsifying and forms a microemulsion spontaneously with aqueous fluids in the gastrointestinal tract, making it less dependent on bile for absorption. The result is a sig-niflcantly greater rate and extent of absorption and decreased intraindividual variability in pharmacokinetic parameters. Bioavailability is enhanced owing to better dispersion and absorption and does not require bile excretion. The relative bioavailability of the microemulsion formulation is 60%. Peak concentrations generally are reached within 1.5 to 2 hours after oral administration. The terminal half-life is 8.4 hours. 

Polar surface area Blood flow Bacteria Liver uptake and bile excretion... 

By a similar type of reasoning, it could be shown that the total clearance can also be written as the sum of metabolic and excretion clearances for each organ or tissue where metabolism or excretion of a drug takes place. Eor example, the overall clearance for a drug that undergoes hepatic metabolism as well as renal and bile excretion would become... 

PO/IM/IV., seven day half -life, 100% Gl absorption, 97% protein bound, distribution similar to digoxin, liver metabolism, bile excretion. 

Total concentration of muraglitazar plus all metabolites (muraglitazar equivalents). Calculated based on theoretical bile excretion volume in 0-24 or 0-48 h for animals and 0-8 h for humans. The bile concentration in rats was an assumption only since there is no gallbladder in the rat. 

Feces and Bile Excretion in feces represented more than 95% of the recovered radioactive dose in rats, dogs, monkeys, and humans. Muraglitazar was one of the abundant components present in feces from all species. The HPLC-radiochromatograms of pooled bile samples from rats, monkeys, and humans are shown in Fig. 18.3. The relative distribution of metabolites in urine and feces (as % of dose) is shown in Table 18.7. 

FIGURE 8.3 Suppression of bile excretion and the ATP level in liver ischemia and their recoveries during recirculation. (O) = bile flow rate ( ) cellular level of ATP in the rat liver. Original work reproduced from Kamiike et al. (1985) with kind permission from Wolters Kluwer Health. 

Kamiike W, Nakahara M, Nakao K, Koseki M, Nishida T, Kawashima Y, Watanabe F, Tagawa K (1985) Correlation between cellular ATP level and bile excretion in the rat liver. Transplantation 39, 50-5. 

The tellurium excretion patterns depend mainly on the chemical forms and the administration mode of the compounds. Excretion is greater in urine than in feces when tellurium is given parenterally, but orally ingested tellurium salts are excreted mainly in the feces [22]. About 60-80% of ingested tellurite is rapidly excreted in feces by rats. Tellurium moves with bile excretion to the intestine. Small amounts of absorbed elemental tellurium and tellurite are exhaled (about 0.1%) presumably as dimethyltelluride producing a garlic-like odor noted in humans [23]. 

Lecithin, a common name for PC, is a natural emulsifier found in egg yolk. It is present in bile and helps prevent the formation of gallstones by stabilizing bile cholesterol. In addition, lecithin present in bile excreted into the intestine aids in fat digestion. Lecithin is widely used in foods such as margarines and salad dressings to stabilize the fat components, thus preventing the separation of the fat and water components. In addition, lecithin is used in non-food products such as soaps, paints and cosmetics (Brown, 1990). 

The major route of excretion of manganese is through the bile excretion. The amount of manganese excreted in the urine is negligible. 

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