Biliary-renal excretion

Bile ducts Various intravenous cholegraphic agents, e.g., iodipamide Biligrafin Anion transport Lin SK et al (1977) Iodipamide kinetics Capacity-limited biliary excretion with simultaneous pseudo-first-order renal excretion. J Pharm Sci 66 1670-1674... 

Renal excretion is the most important endosulfan elimination route in humans and animals. Biliary excretion has also been demonstrated to be important in animals. Estimated elimination half-lives ranged between approximately 1 and 7 days in adult humans and animals. Endosulfan can also be eliminated via the breast milk in lactating women and animals, although this is probably a relatively minor elimination route. No studies were located regarding known or suspected differences between children and adults with respect to endosulfan excretion. 

Peak plasma levels are reached about 1.5 h after oral ingestion, the maximum concentrations being in the order of 2 - 3 ng equivalents/ml (parent drug + metabolites) for an oral 1 mg dose. The elimination from the plasma is biphasic and proceeds with mean half-lives of 6 h (a-phase) and 50 h ((3-phase). Similar elimination half-lives are obtained from the urinary excretion. The cumulative renal excretion is practically the same after oral and intravenous administration and amounts to 6 - 7 % of the radioactivity dosed. The main portion of the dose, either oral or intravenous, is eliminated by the biliary route into the faeces. The kinetics of bromocriptine has been demonstrated to be linear in the oral dose range from 2.5 to 7.5 mg. 

Hydroxylated metabolites are conjugated as glucuronides and sulfates. The balance of products in this last step and their distribution between urine and feces distinguishes the metabolism between humans, rats, and rabbits (Baldwin and Hutson 1980 Bedford et al. 1975b Hutson 1981 Hutson et al. 1975), as discussed in Section 2.3.4. Similarly, studies in lactating cows ingesting radio-labeled endrin in the diet for 21 days suggest metabolic pathways similar to those in rats and rabbits with apparent differences between the 3 species attributed more to differences in biliary versus renal excretion (Baldwin et al. 1976). 

Table III shows the amounts of free- and conjugated-PCP excreted from each of the biliary, renal and branchial routes.

The organs of extraction are generally the liver (hepatic clearance - metabolism and biliary excretion CIh) and the kidney (renal excretion, CIr) and the values can be summed together to give an overall value for systemic clearance (Cls) ... 

Metaboiism/Excretion- Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. 

Norfloxacin - Absorption is rapid. Food or dairy products may decrease absorption. Steady-state norfloxacin levels will be attained within 2 days of dosing. Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. Renal excretion occurs by glomerular filtration and tubular secretion. In healthy elderly volunteers, norfloxacin is eliminated more slowly because of decreased renal function. In patients with Ccr rates 30 mL/min/1.73 m or less, the renal elimination decreases so that the effective serum half-life is 6.5 hours dosage alteration is necessary. 

Payan JP, Fabry JP, Beydon D, et al. 1991. Biliary excretion of hexachloro-1,3-butadiene and its relevance to tissue uptake and renal excretion in male rats. J AppI Toxicol 11 437-442. 

Active transporters are thought to play an important role in the pharmacokinetics of drugs, not only because they can regulate the permeability of drugs as substrate-specific efflux or influx pumps, but also because of their widespread presence across in vivo membrane systems, from the intestinal epithelia to the BBB. Generally speaking, the absorption direction transporters tend to have narrower substrate specificity than the excretion direction transporters. Active transporters also play a significant role in biliary and renal excretion. 

Pharmacokinetics Well absorbed following oral administration. Protein binding 10%-15%. Eliminated through metabolism, biliary excretion, and renal excretion. Half-life 3-4 hr... 

The renal excretion of compounds can also be affected by the presence of a chiral center, probably as a result of active secretion. For example, with the drug terbutyline, the ratio for the excretion of the (+) to (—) enantiomers was found to be 1.8. Similarly, biliary excretion of compounds may show stereoselectivity. 

Because of the kidney s involvement in the excretion of hydrophilic compounds and because most of the substrates of P-gp are hydrophobic compounds that are likely to be cleared mainly by biliary excretion or intestinal secretion, comparably fewer studies have been performed with the isolated perfused kidney. The isolated perfused rat kidney model was used to demonstrate that digoxin is actively secreted by P-gp located on the luminal membrane of renal tubular epithelial cells and that clinically important interactions with qui-nidine and verapamil are caused by the inhibition of P-gp activity in the kidney (332). These results provide an excellent example of how the isolated perfused kidney model can be used to definitively conclude that P-gp-mediated efflux is involved in the renal excretion of a compound and also to elucidate possible DDIs that might arise in the kidney following coadministration of P-gp sub strates/inhibitors. 

Adverse effects The most common of these are headache, diarrhea, and nausea. Other untoward effects are weight loss, allergic reactions including a flu-like syndrome, skin rash, alopecia, and hypokalemia. Leflunomide is teratogenic in experimental animals, and is therefore contraindicated in pregnancy, and in women of childbearing potential. It should be used with caution in patients with liver disease, because it is cleared by both biliary and renal excretion. Cholestyramine increases the clearance of leflunomide. 

The degree of biliary excretion is species dependent. Generally, mice, rats, and dogs have a better biliary excretion than rabbits, monkeys, and humans [118]. Gd-BOPTA has a 0.6 % biliary excretion in humans, the remainder being excreted in urine [119]. Gd-EOB-DTPA has a biliary excretion of 43.1-53.2%, a renal excretion of 41.6-51.2%, and an extrahepatic recirculation of about 4% in humans [120]. In various animals, excretion is slightly different. For example, the biliary excretion of Gd-BOPTA in rats is 55% and in rabbits is 25% [121], Gd-EOB-DTPA has a 63-80% biliary excretion in rats and a 32-34% excretion in monkeys [122]. 

The physiological mechanisms by which phenylbutazone is cleared from the body in the horse have not been well described. In one study, renal clearance accounted for only 25% of the total drug administered (Lees et al 1985). It has been hypothesized that biliary excretion with subsequent fecal elimination represents the primary clearance mechanism of phenylbutazone in the horse (Lees et al 1985). Renal excretion, of an as yet unidentified phenylbutazone metabolite, may also account for a proportion of total body clearance of the compound. 

The tetracyclines, apart from doxycycline and minocycline, are slowly eliminated by renal excretion (glomerular filtration). Their slow elimination can be attributed to enterohepatic circulation whereby drug excreted by the liver in bile is reabsorbed from the intestine. The half-life of oxytetracycline differs widely between animal species goat (3.4 h), cattle (4.0 h), sheep (5.2 h), dog (6.0 h), pig (6.0 h), donkey (6.5 h), horse (9.6 h), and red-necked wallaby (.Macropus rufogriseus) (11.4 h). Doxycycline, unlike other tetracyclines, is eliminated by biliary excretion and diffusion into the intestine. The half-life of doxycycline is relatively short in dogs (7.0 h) and cats (4.6 h) compared with human beings (16 h). The half-life of doxycycline in chickens (4.8 h) is shorter than in turkeys (10 h) (Santos et al, 1996). Minocycline is mainly eliminated by hepatic metabolism. 

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