Biliary system excretion

Rapidly, completely absorbed from the GI tract. Protein binding 90%-94%. Metabolized in the liver to active metabolite. Primarily eliminated in feces via biliary system excreted in urine. Not removed by hemodialysis. Half-life 12 hr. 

Table V contains data for two model substances, p-aminohippurate (PAH) and phenol red. Consideration of the highest values in this table tells you where the major portions of the substances appear. For example, urine and bile show the largest concentrations of PAH and phenol red. Both compounds appear in significant concentrations in the kidney while the values in muscle, brain and cerebrospinal fluid (CSF) are invariably lower than the values seen in plasma. The values in parentheses (Table V) are percent of the administered dose in a given tissue or fluid compartment. They add to the previous information by revealing the overall importance of a particular compartment in the disposition of a substance. For example, while the hepatic concentrations of PAH and phenol red at 4 hrs. are only about 2-fold those of plasma, the large size of the shark liver relative to its body weight, typically about 10%, leads to the appearance of 30-40% of these substances in the liver. The relative handling of these compounds by the urinary and biliary system is obvious from considering the percentage figures. Thus in 24 hours phenol red is about equally distributed in the bile and urine (38 vs 31%) the urinary route is the dominant route of excretion of PAH, i.e., 56 vs 2%.

Excretion, along with metabolism and tissue redistribution, is important in determining both the duration of drug action and the rate of drug elimination. Excretion is a process whereby drugs are transferred from the internal to the external environment, and the principal organs involved in this activity are the kidneys, lungs, biliary system, and intestines. 

Rapidly, completely absorbed. Protein binding greater than 99%. Undergoes minor hepatic metabolism to inactive metabolite. Excreted unchanged in urine and in the feces through the biliary system. Not removed by hemodialysis. Half-life 9 hr. 

Pharmacokinetics Minimal absorption after PO, inhalation, or nasal administration. Absorbed portion excreted in urine or by biliary system. Half-life 80-90 min,... 

Pharmacokinetics Rapidly absorbed after PO administration. Protein binding 98%. Undergoes first-pass metabolism in the liver to active metabolites. Excreted in urine and biliary system. Minimally removed by hemodialysis. Half-life 5-9 hr. 

Pharmacokinetics Readily absorbed from the GI tract (duodenum) after IM or subcutaneous administration. Metabolized in the liver. Excreted in urine eliminated by biliary system. Onset of action with PO form, 6-10 hr with parenteral form, hemorrhage controlled in 3-6 brand PT returns to normal in 12-14 hr. 

Pharmacokinetics Poorly absorbed after IM administration. Protein binding 27%-35%. Metabolized in liver. Excreted in urine. Eliminated in feces via biliary system. Not removed by hemodialysis. Half-life 8.5-9.6 hr (half-life is increased with impaired renal function). 

Mechanism of Action An HMG-CoA reductase inhibitor that interferes with cholesterol biosynthesis by preventing the conversion of HMG-CoA reductase to meva-lonate, a precursor to cholesteroh Therapeutic Effect Lowers serum LDL and VLDL cholesterol and plasma triglyceride levels increases serum HDL concentration. Pharmacokinetics Poorly absorbed from the G1 tract. Protein binding 50%. Metabolized in the liver (minimal active metabolites). Primarily excreted in feces via the biliary system. Not removed by hemodialysis. Half-life 2.7 hr. 

First-pass metabolism (first-pass effect) The passage of the drug from the portal circulation into hepatocytes and conversion there into metabolites. These metabolites may have a pharmacological profile different from that of the parent drug. They are typically then excreted by the hepatocytes into the biliary system and pass back into the small bowel where enterohepatic recirculation may occur (e.g., benzodiazepines, bupropion, nefazodone, neuroleptics, tricyclic antidepressants). 

The principal objective of drug metabolism is to make a drug available for excretion by urine or bile. The renal and biliary systems can excrete water-soluble molecules, whereas water-insoluble drugs must first be converted to a soluble form before they can be excreted. Drug metabolism, therefore, is principally, but not exclusively, of importance for drugs that are non-polar. Metabolism usually results in inactivation of the drug but there are exceptions, e.g. diazepam is metabolised to an active metabolite desmethyidiazepam, which has a much longer duration of action than the parent compound. 

All thiazides can be administered orally, but there are differences in their metabolism. Chlorothiazide, the parent of the group, is not very lipid-soluble and must be given in relatively large doses. It is the only thiazide available for parenteral administration. Chlorthalidone is slowly absorbed and has a longer duration of action. Although indapamide is excreted primarily by the biliary system, enough of the active form is cleared by the kidney to exert its diuretic effect in the DCT. 

Vinblastine is an alkaloid derived from the periwinkle plant Vinca rosea. Its mechanism of action involves inhibition of tubulin polymerization, which disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death. Vinblastine and other vinca alkaloids are metabolized by the liver P450 system, and the majority of the drug is excreted in feces via the biliary system. As such, dose modification is required in the setting of liver dysfunction. The main adverse effects are outlined in Table 54-4, and they include nausea and vomiting, bone marrow suppression, and alopecia. This agent is also a potent vesicant, and care must be taken in its administration. It has clinical activity in the treatment of Hodgkin s... 

Chlortetracycline has, in many respects, a pharmacological profile similar to that of oxytetracycline. Similarly to other tetracyclines, the main excretory routes are through the urinary system, biliary system, and intestine. Its higher biliary excretion rate makes chlortetracycline a better choice than oxytetracycline for liver infections. 

The rate-limiting step for cholesterol synthesis is the production of mevalonate from 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) by the enzyme HMG-CoA reductase. Cholesterol synthesised in the hep-atocyte can be further metabolised by lecithin cholesterol acyl transferase (LCAT) to cholesterol ester, which is packaged into lipoproteins and secreted into the bloodstream. Alternatively, it can be excreted via the biliary system either as a neutral lipid or following conversion to bile acids. 

Example Methylphenidate HC1 (Ritalin, Concerta) CSS II Route PO, IV Pregnancy category C Pharmacokinetic Incompletely absorbed from GI tract metabolized in liver excreted in urine and feces via biliary system... 

Biliary GSH excretion occurs through an electrogenic Na+-independent ATP-independent canalicular transport system which is czs-inhibited and trans-stimulated by certain organic anions and induced by phenobarbital [67]. 

Under physiological conditions there is a very low biliary GSSG excretion (0.4 nmol min g rat liver) [61]. GSH and GSSG are also released from extrahepatic tissues, such as the heart, although at a much lower rate [71]. Erythrocytes exhibit two transport systems to export GSSG - both ATP-dependent -but they lack GSH efflux capacity [72,73]. 

Bile acid synthesis plays an important role in maintaining cholesterol homeostasis, because cholesterol breakdown to bile acids and their subsequent excretion via the biliary system accounts for the majority of cholesterol... 

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