Excretion Biliary

In the canalicular membrane, several ABC transporters such as MDR1 (multidrug resistance 1), MRP2 (multidmg resistance-associated protein 2), BSEP (bile salt 

T ransporter Gene symbol Chromosome Reference accession (mRNA) Amino acids Transmembrane domains Tissue distribution Cellular localization a o H Substrates  

MDR1 ABCB1 7q21 NM 000927 1280 12 Liver, brain, kidney, intestine, and so on Apical Neutral and cationic hydro- philic drugs such as anti- 

BCRP ABCG2 4q22 NM 004827 655 6 Various organs Apical Mitoxantrone, topotecan, E-sul, DHEAS, imatinib, pita-vastatin, and so on 

BSEP ABCB11 2q24 NM 003742 1321 12 Liver Apical Bile acids, doxorubicin, fexofenadine, and pravastatin 

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Klaassen, C. D., Watkins, J. B. (1984). Mechanisms of bile formation, hepatic uptake, and biliary excretion. Pharmacol. Rev. 36, 1-67. 

The co-administration of drugs which inhibit the transporters involved in biliary excretion can reduce the biliary excretion of drugs which are substrates of the transporter, leading to elevated plasma concentrations of the drugs. For example, biliary and urinary excretion of digoxin, both mediated by P-gp, are inhibited by quinidine which is an inhibitor of P-gp. 

Gall bladder Various oral cystographic agents, e.g., iopanoic acid Telepaque etc. Anion transport Urich K, Speck U (1991) Biliary excretion of contrast media. Progr Pharmacol Clin Pharmacol 8 307-322... 

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. 

Methods of detection, metabolism, and pathophysiology of the brevetoxins, PbTx-2 and PbTx-3, are summarized. Infrared spectroscopy and innovative chromatographic techniques were examined as methods for detection and structural analysis. Toxicokinetic and metabolic studies for in vivo and in vitro systems demonstrated hepatic metabolism and biliary excretion. An in vivo model of brevetoxin intoxication was developed in conscious tethered rats. Intravenous administration of toxin resulted in a precipitous decrease in body temperature and respiratory rate, as well as signs suggesting central nervous system involvement. A polyclonal antiserum against the brevetoxin polyether backbone was prepared a radioimmunoassay was developed with a sub-nanogram detection limit. This antiserum, when administered prophylactically, protected rats against the toxic effects of brevetoxin. 

These studies represent the first report of the metabolism of brevetoxins by mammalian systems. PbTx-3 was rapidly cleared from the bloodstream and distributed to the liver, muscle, and gastrointestinal tract. Studies with isolated perfused livers and isolated hepatocytes conflrmed the liver as a site of metabolism and biliary excretion as an important route of toxin elimination. [ H]PbTx-3 was metabolized to several compounds exhibiting increased polarity, one of which appeared to be an epoxide derivative. Whether this compound corresponds to PbTx-6 (the 27,28 epoxide of PbTx-2), to the corresponding epoxide of PbTx-3, or to another structure is unknown. The structures of these metabolites are currently under investigation. 

Finally, the fact that anthocyanins can reach the brain represents a beginning of an explanation of the purported neuroprotection effects of anthocyanins. Anthocyanins may be eliminated via urinary and biliary excretion routes. " The extent of elimination of anthocyanins via urine is usually very low (< 0.2% intake) in rats and in humans, indicating either a more pronounced elimination via the bile route or extensive metabolism. As mentioned earlier, in the colon, non-absorbed or biliary excreted anthocyanins can be metabolized by the intestinal microflora into simpler break-down compounds such as phenolic acids that may be (re)absorbed and conjugated with glycine, glucuronic acid, or sulfate and also exhibit some biological... 

Molecular size can be a further limiting factor in oral absorption [54]. The Lipinski Rule-of-5 proposes an upper limit of molecular weight (MW) of500 as acceptable for orally absorbed compounds [25]. High-MW compounds tend to undergo biliary excretion. Size and shape parameters are generally not measured, but rather calculated. A measured property is the so-called cross-sectional area, which is obtained from surface activity measurements [55]. 

Palmer 1989 Robinson et al.1983). However, the ratio was almost certainly affected by initial chelation with Ca-DPTA, followed by daily intravenous therapy with the chelating agent, Zn-DPTA, treatments that would have increased the urinary excretion of americium (Breitenstein and Palmer 1989). The above not withstanding, the observations made on this subject demonstrate that fecal excretion was an important pathway of excretion in this subject long after mechanical clearance of americium from the respiratory tract would have been complete. This is consistent with observations made in nonhuman primates that show that americium is excreted into bile (see Section 3.4.4.4). However, the extent to which the biliary excretion pathway in humans might resemble that of nonhuman primates is not known. 

The large contribution of the fecal route to excretion of absorbed americium appears to be the result of excretion of americium into the bile. In monkeys that received an intravenous injection of americium citrate,241 Am was detected in gall bladder bile and its concentration increased as the relative rate of fecal excretion increased over time post injection (Durbin 1973). Durbin (1973) estimated that at bile production rates similar to humans, biliary excretion could have accounted for most, if not all, of the fecal excretion of americium observed in the monkeys. 

Experiments with rats given oral doses of tritiated food-grade mineral oil provide supporting evidence that the absorption of hydrocarbons in mineral oils is limited. Five hours after dosing with 0.66 mL/kg of tritiated mineral oil ("liquid petrolatum U.S.P."), -75% of the administered radioactivity remained in the alimentary tract, and only 3% of the administered radioactivity was accounted for by radioactivity in other parts of the rat carcass (Ebert et al. 1966). About 80% of the administered radioactivity was recovered in feces during the first 2 days after treatment, and over 90% of the radioactivity in the feces was in the form of mineral oil. These data are consistent with the hypothesis that ingested mineral oil was poorly absorbed. Neither biliary excretion nor enterohepatic circulation of mineral oils was measured in this study, and thus, any quantitative estimates of the extent of absorption based on these data should be viewed as tentative. 

Experiments with rats given oral or intraperitoneal doses of tritiated mineral oil (Liquid Petrolatum USP) indicate that orally administered hydrocarbons in mineral oil are predominately excreted rapidly, unchanged, and unabsorbed in the feces and that absorbed mineral oil is slowly excreted in the feces (presumably via biliary excretion) (Ebert et al. 1966). 

Studies with rats treated orally with triaryl or trialkyl phosphate esters (which may be found in organophosphate ester hydraulic fluids) indicate that these compounds and their metabolites are readily excreted in the urine, bile, feces and, to a limited extent, in expired air (Kurebayashi et al. 1985 Somkuti and Abou-Donia 1990a Suzuki et al. 1984a Yang et al. 1990). Urinary excretion of metabolites appears to be the predominant elimination route in rats for tri-ort/zo-cresyl phosphate and tri-para-cresyl phosphate, but biliary excretion of parent material and metabolites is also important (Kurebayashi et al. 1985 NTP... 

Within 8 days of an intraperitoneal dose of 0.66 mL/kg tritiated mineral oil to rats, 11% of administered radioactivity was excreted in the feces, predominately in the form of mineral oil (95%) (Ebert et al. 1966). Urine during the same time frame after intraperitoneal administration contained about 8% of the administered radioactivity, but in chemical forms other than mineral oil. The detection of radioactivity in the feces after intraperitoneal administration suggests that significant biliary excretion of absorbed mineral oil can occur. 

Fig. 2 Various routes and pathways by which a drug may be input into the body. The position of one lung is distorted to emphasize that the lungs are in an excellent position for cleansing the blood. The diagram is especially useful in explaining the first-pass effect following oral dosing, for which drug absorbed from the small intestine or stomach must first pass through the liver and, therefore, is subject to metabolism or biliary excretion before reaching the sampleable blood. (From Ref. 2.)...

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. 

Several studies in rats have shown that certain acidic and basic compounds can be actively secreted into the bile. Thus, one might expect to see saturation of the biliary excretion process, although data in humans describing this phenomenon have not, as yet, been reported for orally dosed drugs. 

Lead is also eliminated in the bile (Klaassen and Shoeman 1974). In the rat, excretion occurs in the urine, with greater excretion in the feces following intravenous administration (Castellino and Aloj 1964 Klaassen and Shoeman 1974 Morgan et al. 1977). As the dose increases, the proportion of the lead excreted into the gut via bile increases, then plateaus at 3 and 10 mg/kg (Klaassen and Shoeman 1974). Biliary excretion of lead is suggested to be a saturable process (Gregus and Klaassen 1986). Excretion of lead in the bile by dogs amounted to approximately 2% of that by rats, and biliary excretion of lead by rabbits amounted to approximately 40% of that by rats (Klaassen and Shoeman 1974). 

Lead undergoes biliary excretion in the dog, rat, and rabbit biliary excretion is presumed to contribute to fecal excretion of lead in humans (EPA 1994b Klaassen and Shoeman 1974 O Flaherty 1993). The mechanism of biliary excretion has not been elucidated. 

Gregus Z, Klaassen CO. 1986. Disposition of metals in rats A comparative study of fecal, urinary, and biliary excretion and tissue distribution of eighteen metals. Toxicol Appl Pharmacol 85 24-38. 

Klaassen CD, Shoeman DW. 1974. Biliary excretion of lead in rats, rabbits, and dogs. Toxicol Appl Pharmacol l(9) 434-446. 

The liver plays an important role in determining the oral bioavailability of drags. Drag molecules absorbed into the portal vein are taken up by hepatocytes, and then metabolized and/or excreted into the bile. For hydrophilic drugs, transporters located on the sinusoidal membrane are responsible for the hepatic uptake [1, 2]. Biliary excretion of many drags is also mediated by the primary active transporters, referred to as ATP-binding cassette transmembrane (ABC) transporters, located on the bile canalicular membrane [1, 3-5], Recently, many molecular biological... 

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