Biliary Transport Route

A fraction of the intestinaly excreted polymer may be transported into the intestinal lumen with the bile. Bile is produced by the liver parenchymal cells (hepatocytes) by active secretion in the sense that the hepatocytes transform and transport blood components, bile acids and bilirubin into the bile canaliculi. There are some indications that macromolecules and even particles, e.g. colloidal mercuric sulfite, colloidal Ag, can be eliminated from blood in the bile although this elimination is slow. De 

Duve points to the presence in rat bile of sigm ficant amounts of all lysosomal hydrolases, as support for the suggestion that the particles and macromolecules may appear in the bile as a consequence of emptying of some secondary lysosomes by extrusion In this way, even polymers larger than the threshold of glomerular filtration could be exocytosed into the bile and excreted via the intestine out of the body, if they are formerly pinocytosed by the hepatocytes (Fig. 7). 

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Pharmacokinetics Unlike most of the alkylating agents, cyclophosphamide and ifosfamide are preferentially administered by the oral route. Minimal amounts of the parent drug are excreted into the feces (after biliary transport), or into the urine by glomerular filtration. 

Excretion is the elimination of the molecule from the organism by one of several routes. The urine is the major route, but expired air and bile may also be used. Urinary excretion involves filtration, passive diffusion, and active transport. Biliary excretion involves active transport, and there is a molecular weight threshold for compounds, above which excretion by this route becomes more important. Biliary excretion may lead to enterohepatic recirculation. Excretion by these routes can be saturated, leading to accumulation. 

The cobalamins are excreted in urine, bile, and feces. Intact cobalamin molecules are the predominant forms in urine. Urinary excretion is highly variable, but it averages 150 ng/d and is somewhat higher in smokers than nonsmokers. The principal excretory route is bile. Cobalamins destined for biliary excretion may be transported to the liver by TCI and TCIII. The liver is the only tissue that takes up the TCI-cobalamin complex. 

Metabolism in pediatric patients can be quite different from adults. In the very young infant, drug uptake by the liver is decreased due to reduced transport proteins. The biliary excretion of antibiotics with dual routes of elimination suggests that hepatic transport maturation is even slower than glomerular filtration or renal transport maturation. Overall, mixed function oxidases are present at 30-50% of adult activity, while individual enzymes may be less than 5% of adult activity. In particular, isoenzymes of CYP 2C9 and 1A2 have greatly reduced activity in neonates however, there is a rapid increase in 2C9 activity in the first weeks of life. After birth. Phase I and II enzymes have a programmed order of expression, which is different for each isoenzyme. Some isoenzymes increase in days, others over weeks, and stUI others over months. 

Chapter 4), secretion into the bile can be a major route of excretion. Excretion into the bile is usually, although not exclusively, an active process and there are three specific transport systems, one for neutral compounds, one for anions and one for cations. Quaternary ammonium compounds may be actively secreted into the bile by a separate process. Compounds which undergo biliary excretion have been divided into classes A, B and C. Class A compounds are excreted by diffusion and have a bile to plasma ratio of around 1 class B compounds are actively secreted into bile and have a bile to plasma ratio of... 

Chronic treatment with the enzyme inducer phenobarbital enhances the biliary excretion of drug molecules and their metabolites by increasing liver size, bile flow, and more efficient transport into the bile. This behavior is not shared by all inducers of the CYP450 monooxygenases. The route of administration also may influence excretion pathways. Direct administration into the portal circulation might be expected to result in more biliary excretion than could be expected via the systemic route. 

Transporters are involved in biliary and renal excretions that are the two common routes of drug elimination. In the liver, a drug is first taken up into hepatocytes, then either secreted back to the systemic circulation or excreted to the bile in an intact form or as metabolites via Phase I and/or Phase II enzymes. Given the involvement of transporters in both uptake at the sinusoidal membrane and efflux at the sinusoidal and canulicular membranes (Fig. 6.1c), the hepatic clearance can be expressed based on well-stirred model as the following equation (Shitara et al., 2005 Yamazaki et al., 1996) ... 

Flavonoids are not transported through in the circulatory system and reach body tissues instead, their secondary metabolites formed in the small intestine and hepatic cells elicit antioxidant effects. These reactions favor their excretion via biliary and renal, being the elimination in bile the most important route of elimination for most flavonoids (Cre-spy et al 2003). Flavonoid secondary metaboHtes can be detected in the blood and urine after its ingestion, but only very small fraction of nonconjugated flavonoids in their original form can be found. This implies that these flavonoid secondary metaboHtes rather than the native flavonoids are responsible for the beneficial biological effects in the body (Donovan et al 2006)... 

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