Biliary secretion

Biliary Excretion. The effects of significant hepatic extraction as a result of biliary secretion, with or without metabolism, would be expected to follow the same principles just outlined for hepatic metabolism. In fact, a whole class of compounds that serve as biliary contrast agents for radiological examination depend on significant first-pass biliary secretion to be effective. 

The Leggett Model simulates lead biokinetics in liver with two compartments the first simulates rapid uptake of lead from plasma and a relatively short removal half-life (days) for transfers to plasma and to the small intestine by biliary secretion a second compartment simulates a more gradual transfer to plasma of approximately 10% of lead uptake in liver. Different transfer rates associated with each compartment are calibrated to reproduce patterns of uptake and retention of lead observed in humans, baboons, and beagles following intravenous injection, as well as blood-to-liver concentration ratios from data on chronically exposed humans. Similarly, the Leggett Model simulates lead biokinetics in three compartments of soft tissues, representing rapid, intermediate, and slow turnover rates (without specific physiologic correlates). 

The liver plays a decisive role in the cholesterol metabolism. The liver accounts for 90% of the overall endogenic cholesterol and its esters the liver is also impli-cated in the biliary secretion of cholesterol and in the distribution of cholesterol among other organs, since the liver is responsible for the synthesis of apoproteins for pre-p-lipoproteins, a-lipoproteins, and P-lipoproteins which transport the secreted cholesterol in the blood. In part, cholesterol is decomposed by intestinal micro-flora however, its major part is reduced to coprostanol and cholestanol which, together with a small amount of nonconverted cholesterol, are excreted in the feces. 

Although the pressure to screen large numbers of compounds quickly has led to the rapid development of in silico and in vitro assays, the sheer number and complexity of the processes involved in determining the disposition of any particular compound means that in vivo studies are still required to provide assurance that the important processes are modeled with sufficient accuracy [4-6], and indeed, that the potential contribution of processes for which there are no good in vitro models (e.g., biliary secretion) are adequately assessed. 

Diphenolmethane derivatives (p. 177) were developed from phenolphthalein, an accidentally discovered laxative, use of which had been noted to result in rare but severe allergic reactions. Bisac-odyl and sodium picosulfate are converted by gut bacteria into the active colon-irritant principle. Given by the enteral route, bisacodyl is subject to hydrolysis of acetyl residues, absorption, conjugation in liver to glucuronic acid (or also to sulfate, p. 38), and biliary secretion into the duodenum. Oral administration is followed after approx. 6 to 8 h by discharge of soft formed stooL When given by suppository, bisacodyl produces its effect within 1 h. 

Species differences in the metabolism of propachlor are summarized in Table II. All species studied metabolized propachlor in the MAP. Obvious, but unexplained differences are that the rat excreted no cysteine conjugate and the chicken formed no methylsulfonyl-containing metabolites. The absence of methylsulfonyl formation by chickens is thought due to the low biliary secretion of first pass metabolites. The ruminant (sheep) excreted large amounts of cysteine conjugate in urine which is also not explained. We do not know if the intestinal flora are involved in the formation of the methylsulfonyl acetanilides isolated from sheep urine. 

Knecht KT, Mason RP. 1988. In wVo radical trapping and biliary secretion of radical adducts of carbon tetrachloride-derived free radical metabolites. Drug Metab Dispos 16 813-817. 

Liver disease or injury may impair bile secretion and thereby lead to accumulation of certain drugs, for example probenecid, digoxin, and diethylstilbestrol. Impairment of liver function can lead to decreased rates of both drug metabolism and secretion of drugs into bile. These two processes, of course, are frequently interrelated, since many drugs are candidates for biliary secretion only after appropriate metabolism has occurred. 

Decreases in biliary excretion have been demonstrated at both ends of the age continuum. For example, ouabain, an unmetabolized cardiac glycoside that is secreted into the bile, is particularly toxic in the newborn. This is largely due to a reduced ability of biliary secretion to remove ouabain from the plasma. 

Digestive Decreased salivation reduced tone and motility in the gastrointestinal tract decrease in vagus-stimulated gastric, pancreatic, intestinal, and biliary secretions... 

Mechanism of Action A direct thrombin inhibitor that reversibly binds to thrombin-active sites. Inhibits thrombin-catalyzed or thrombin-induced reactions, including fibrin formation, activation of coagulant factors V, VIII, and XIII also inhibits protein C formation, and platelet aggregation. Therapeutic Effect Produces anticoagulation. Pharmacokinetics Following IV administration, distributed primarily in extracellular fluid. Protein binding 54%. Metabolized in the liver. Primarily excreted in the feces, presumably through biliary secretion. Half-life 39-51 min. 

Minimally absorbed from the GI tract. Protein binding 90%-96%. Metabolized in the liver. Excreted in feces by biliary secretion. Half-life 15 hr. 

Pharmacokinetics Rapidly absorbed from the G1 tract, ffighest concentration is in the liver, spleen, and kidney. Protein binding 30%-50%. Reenters the intestinal tract by biliary secretion and is reabsorbed from the intestines. Partially metabolized in the liver. Eliminated primarily in feces. 

To investigate further the chemical characteristics of potential alternative emulsifiers, the water-soluble fractions (WSFs) of each emulsifier were measured [61]. The samples were analyzed for total recovered hydrocarbons (TRH) in the C10-C36 region and PAHs [3, 62]. The chemical analysis of the emulsifier WSFs did not detect PAHs. Consequently, in the future, use of low-fluorescence emulsifiers in the reformulated Syndrill 80 20 (Mod) will allow the measurement of biliary fluorescence as a biomarker of exposure in field-caught fish attracted to cutting piles, with any detected fluorescence eliminating the drilling mud Syndrill 80 20 (Mod) as a source of fluorescent metabolites in the biliary secretions. 

Hexachlorobutadiene is a nephrotoxic industrial chemical, damaging the pars recta of the proximal tubule. Initial conjugation with GSH is necessary, followed by biliary secretion and catabolism resulting in a cysteine conjugate. The conjugate is reabsorbed and transported to the kidney where it can be concentrated and becomes a substrate for the enzyme p-lyase. This metabolizes it into a reactive thiol, which may react with proteins and other critical macro molecules with mitochondria as the ultimate target. The kidney is sensitive because the metabolite is concentrated by active uptake processes (e.g., OAT 1), which reabsorb the metabolite into the tubular cells. 

Drug metabolism, renal tubular secretion, and biliary secretion are usually mediated by metabolizing enzymes or transporter proteins. These protein systems usually possess good substrate selectivity with finite capacities, which are described by the Michaelis-Menten equation,... 

Morphine decreases the activity of the entire gastrointestinal tract in that it reduces the secretion of hydrochloric acid, diminishes the motility of the stomach, and increases the tone of the upper part of the duodenum. These actions may delay passage of the stomach contents into the duodenum. Both pancreatic and biliary secretions are diminished, which may also hinder digestion. In the large... 

Elimination is predominantly renal, with about 80% of an oral dose being excreted as urinary metabolites. The remainder is excreted in the faeces and originates primarily from biliary secretion [1],... 

The effects of the P-gp inhibitor, GF120918, on the hepatobiliary disposition (biliary excretion) of doxorubicin were determined using a perfused rat liver system (270). Biliary excretion is the rate-limiting process for doxorubicin elimination. In the presence of GF120918, the biliary excretion of doxorubicin and its major metabolite, doxorubicinol, was decreased significantly without alterations in doxorubicin perfusate concentrations or doxombicin and doxorubicinol liver concentrations. In a similar study on the hepatic elimination of other P-gp substrates, including vincristine and daunorubicin, it was reported that canalicular P-gp plays a significant role in the biliary secretion of these compounds (428,429). 

Biliary secretion, however, is the most important route for conjugated metabolites. After secretion into the gut, further metabolism and subsequent reabsorption is possible, due to an increased lipophilicity of the metabolite as is the case with methylsulfinyl and methylsulfonyl metabolites72,63 (see Scheme 3). This may give rise to an enterohepatic circulation (re-)absorption - modification in the liver ->excretion through the bile - modification in the intestines. 

Roda A, Aldini R, Grigolo B et al. (1988) 23-Methyl-3a,7b-dihydroxy-5b-cholan-24-oic acid Dose-response study of biliary secretion in rat. Hepatol 8 1571-1576 Paglietti G, Sanna P, Carta A et al. (1994) Choleretic activity of 3-[ring substituted benzotriazol-l(2)yl]alkanoic and alkenoic adds. Farmaco 49 693-702 Peana A, Satta M, Luigi-Moretti MD, Orecchioni M (1994) A study on choleretic activity of Salvia desoleana essential oil. Planta Med 60 478 179... 

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