Routes of elimination

The kidney is an important organ for the excretion of toxic materials and their metaboHtes, and measurement of these substances in urine may provide a convenient basis for monitoring the exposure of an individual to the parent compound in his or her immediate environment. The Hver has as one of its functions the metaboHsm of foreign compounds some pathways result in detoxification and others in metaboHc activation. Also, the Hver may serve as a route of elimination of toxic materials by excretion in bile. In addition to the Hver (bile) and kidney (urine) as routes of excretion, the lung may act as a route of elimination for volatile compounds. The excretion of materials in sweat, hair, and nails is usually insignificant. 

The GI absorption of the dmg after po adrninistration is slow and variable with estimates ranging from 20—55%. Once absorbed, 96% of the dmg is bound to plasma proteins and other tissues on the body. Whereas peak plasma concentrations may be achieved in 3—7 h, the onset of antiarrhythmic action may occur in 2—3 days or more. This may result, in part, from distribution to and concentration of the dmg in adipose tissue, Hver, spleen, and lungs. Therapeutic plasma concentrations are 1—2 p.g/mL, although there appears to be no correlation between plasma concentration and antiarrhythmic activity. The plasma half-life after discontinuation of the dmg varies from 13—103 days. The dmg is metabolized in the Hver and the principal metaboHte is desethylamiodarone. The primary route of elimination is through the bile. Less than 1% of the unchanged dmg is excreted in the urine. The dmg can also be eliminated in breast milk and through the skin (1,2). 

Po adrninistered nifedipine is almost completely absorbed. The onset of action is 20 min and peak effects occur at 1—2 h. The principal route of elimination is through hepatic metaboHsm by oxidation to hydroxycarboxyHc acid and the corresponding lactone. These metaboHtes are pharmacologically inactive. Almost 70—80% of dmg is eliminated in the urine during the first 24 h. About 15% is excreted in the feces. The elimination half-life of nifedipine is about 1—2.5 h (1,98,99). Frequency of occurrence of side effects in patients is about 17% with about 5% requiring discontinuation of therapy (1,98,99). 

The pharmacokinetics of azacitidine shows that it is rapidly absorbed after s.c. administration with the peak plasma concentration occurring after 0.5 h. The bioavailability of s.c. azacitidine relative to i.v. azacitidine is approximately 89%. Urinary excretion is the primary route of elimination of azacitidine and its metabolites. The mean elimination half-lives are about 4 h, regardless of i.v. or s.c. administration. 

Intravenous administration of endosulfan (7 3 ratio of a- and P-isomers) in rabbits produced slower elimination of the a-isomer (Gupta and Ehrnebo 1979). Excretion of the two isomers occurred primarily via the urine (29%) with much less excreted via the feces (2%). Given the earlier evidence in rats and mice describing the principal route of elimination of endosulfan and its metabolite to be via the feces, the differences in the excretion pattern in this study may be attributable to differences in exposure routes, to species differences, or to both. Nevertheless, studies in laboratory animals suggest that both renal and hepatic excretory routes are important in eliminating endosulfan from the body. Elimination of small doses is essentially complete within a few days. 

G. C., Resorption rate, route of elimination, and ultrastructure of the implant site of polylactic acid in the abdominal wall of the rat, J. Biomed. Mater. Res., 7, 155, 1973. 

Estramustine, an oral drug, also inhibits microtubule assembly and has weak estrogenic activity at the estradiol hormone receptors of the cell. Approximately 75% of a dose of estramustine is absorbed.15 The terminal half-life ranges between 20 to 24 hours, with nonrenal excretion as the major route of elimination. This drug is used primarily for the treatment of prostate cancer, but its use is limited by the side effects, which include nausea and vomiting, diarrhea, thromboembolic events, and gynecomastia. 

Daunorubicin is an anthracycline that is sometimes referred to as an antitumor antibiotic. Daunorubicin inserts between base pairs of DNA to cause structural changes in DNA however, the primary mechanism of cytotoxicity is the inhibition of topoisomerase II. The pharmacokinetics are best described by a two-compartment model, with a terminal half-life of about 20 hours. The predominant route of elimination of daunorubicin and hydroxylated metabolites is hepatobiliary... 

This royal-blue-colored drug is an anthracenedione that inhibits DNA topoisomerase II. The pharmacokinetics of mitoxantrone may best be described by a three-compartment model, with an a half-life of 3 to 10 minutes, a 3 half life of 0.3 to 3 hours, and a median terminal half-life of 12 days. Biliary elimination appears to be the primary route of elimination, with less than 10% of the drug eliminated by the kidney.23 Mitoxantrone has shown clinical activity in the treatment of acute leukemias, breast and prostate cancer, and non-Hodgkin s lymphomas. Myelosuppression, mucositis, nausea and vomiting, and cardiac toxicity are side effects of this drug. The total cumulative dose limit is 160 mg/m2 for patients who have not received prior anthracycline or mediastinal radiation. Patients who have received prior doxorubicin or daunorubicin therapy should not receive a cumulative dose greater than 120 mg/m2 of mitoxantrone. Patients should be counseled that their urine will turn a blue-green color. 

Mitomycin C is an alkylating agent that forms cross-links with DNA to inhibit DNA and RNA synthesis. The pharmacokinetics of mitomycin C are best described by a two-compartment model, with an a half-life of 8 minutes and a terminal half-life of 48 minutes.31 Liver metabolism is the primary route of elimination. Mitomycin C has shown clinical activity in the treatment of anal, bladder, cervix, gallbladder, esophageal, and stomach cancer. Side effects consist of myelosuppression and mucositis, and it is a vesicant. 

Anastrozole is a selective nonsteroidal aromatase inhibitor that lowers estrogen levels. The pharmacokinetics of anastrozole demonstrate good absorption, with hepatic metabolism the primary route of elimination and only 10% excreted unchanged by the kidney. The elimination half-life is approximately 50 hours. Anastrozole is used for the adjuvant treatment of postmenopausal women with hormone-positive breast cancer and in breast cancer patients who have had disease progression following tamoxifen. Side effects include hot flashes, arthralgias, osteoporosis/bone fractures, and thrombophlebitis. 

Elimination from the vitreous occurs by one of two pathways. This can be visualized by injecting fluorescent compounds and examining the concentration distribution in frozen sections obtained after a steady state has been established [230]. If the major route of elimination is by means of the re-tina/choroid, at steady state the lowest concentration would be in the vicinity of the retina. The contours observed in frozen sections of the rabbit eye obtained after intravitreal injection of fluorescein exhibit this pattern, with the highest concentration immediately behind the lens (Fig. 16A). Compounds not chiefly eliminated through the retina exit the vitreous by passive diffusion and enter the posterior aqueous, where they are eliminated by the natural production and outflow of aqueous humor. In such a situation, the contours would be perpendicular to the retina, with the highest concentration towards the rear of the vitreous cavity. This appears to be the case for fluorescently labeled dextran polymer, whose contours decrease in concentration toward the hyaloid membrane (Fig. 16B). 

Organic Lead. Urinary lead levels were elevated for 4 days in a man accidentally exposed to an unknown quantity of tetramethyl lead (Gething 1975). Exhalation of the tetraalkyl lead compounds following inhalation exposure is a major route of elimination in humans. At 48 hours postexposure, 40% and 20% of the initially inhaled tetramethyl and tetraethyl lead doses, respectively, were exhaled with low urinary excretion (Heard et al. 1979). 

Administration is by direct injection of 0.05 ml product into the eye (intravitreal injection), initially once every 2 weeks and subsequently once every 4 weeks. Animal studies (rabbits) indicated that the product is cleared from the eye over the course of 7-10 days, with direct nuclease-mediated metabolism representing the primary route of elimination. The most commonly observed side effect is ocular inflammation, which typically occurs in one in every four patients. 

Hens given weekly ip injections for 10 weeks prior to egg laying of 0.1 pg/kg BW had no adverse effects on growth, reproduction, or survival translocation of 2,3,7,8-TCDD to egg yolks indicates that egg laying is an important route of elimination. 

There are pharmacokinetic differences among /1-blockers in first-pass metabolism, serum half-lives, degree of lipophilicity, and route of elimination. Propranolol and metoprolol undergo extensive first-pass metabolism. Atenolol and nadolol have relatively long half-lives and are excreted renally the dosage may need to be reduced in patients with moderate to severe renal insufficiency. Even though the half-lives of the other /J-blockers are much shorter, once-daily administration still may be effective. /J-Blockers vary in their lipophilic properties and thus CNS penetration. 

Another route of elimination is via milk. The secretion of mirex in milk was a major route of elimination for nursing dams given either 1 or 10 mg/kg of mirex on days 2-5 postpartum (Kavlock et al. 1980). The dams excreted 11,000 pig of mirex via the milk during the entire lactation period. 

The main organ involved in PCB metabolism and excretion in fish is the liver. Metabolism of PCBs in fish liver homogenates has been demonstrated (29,30,32) and PCB metabolites are excreted into bile (25,28,34). What is not known is extent to which PCB metabolites excreted in bile are eliminated in feces. Also the role of kidneys, gills, intestine and skin in PCB elimination in fish has not been fully elucidated. The only study on urinary excretion of PCBs was in dogfish sharks and revealed that urine was not a major route of elimination (28). 

Renal clearance of cotinine is much less than the glomerular filtration rate (Benowitz et al. 2008b). Since cotinine is not appreciably protein bound, this indicates extensive tnbnlar reabsorption. Renal clearance of cotinine can be enhanced by np to 50% with extreme urinary acidification. Cotinine excretion is less influenced by urinary pH than nicotine becanse it is less basic and, therefore, is primarily in the unionized form within the physiological pH range. As is the case for nicotine, the rate of excretion of cotinine is influenced by urinary flow rate. Renal excretion of cotinine is a minor route of elimination, averaging about 12% of total clearance. In contrast, 100% of nicotine Ai -oxide and 63% of 3 -hydroxycotinine are excreted unchanged in the urine (Benowitz and Jacob 2001 Park et al. 1993). 

Excretion via faeces is a minor route of elimination, accounting for less than 10% of the administered dose [113,126],... 

Walton et al. (2004) determined the extent of interspecies differences in the internal dose of compounds, which are eliminated primarily by renal excretion in humans. Renal excretion was also the main route of elimination in the test species for most of the compounds. Interspecies differences were apparent for both the mechanism of renal excretion (glomemlar filtration, tubular secretion, and/or reabsorption), and the extent of plasma protein binding. Both of these may affect renal clearance and therefore the magnitude of species differences in the internal dose. For compounds which were eliminated unchanged by both humans and the test species, the average difference in the internal dose between humans and animals were 1.6 for dogs, 3.3 for rabbits, 5.2 for rats, and 13 for mice. This suggests that for renal excretion the differences between humans and the rat, and especially the mouse, may exceed the fourfold default factor for toxicokinetics. 

Genetically caused polymorphisms are known for a number of enzymes, which metabolize chemicals, and are important for the interindividual variability to chemical exposures, especially if the polymorphic pathway represents the major route of elimination. Altered enzyme levels and activities may thus render some individuals more susceptible to exposure to chemicals than the general population. It could therefore be hypothesized that even a very low exposure to a chemical may be associated with various biological responses in such susceptible individuals as altered enzyme levels and activities may influence the individual s ability to detoxify a chemical or increase the conversion of a chemical to a toxic metabolite. 

In the development of most new active substances, it is required to investigate the disposition of the compound and its metabolite(s) and their rates and routes of elimination. This is generally carried out with radiolabelled compound, usually In the United Kingdom, approval of the Administration of Radioactive Substances Advisory Committee (ARSAC) is required for administration of radiolabelled compound to man. The purpose of the submission is to demonstrate that the dose of absorbed radiation is minimised by administration of the lowest dose that is consistent with meeting the objectives of the study. In general, the estimated absorbed radiation dose should be less than 500 xSv, but higher amoimts are permissible if they can be justified. The estimate is based on tissue distribution of radioactivity in animals and the pharmacokinetics in animals and man. 

Metabolism/Excretion- Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism or biliary excretion. Tubular secretion is the major route of elimination. The elimination half-life is approximately 17.6 hours. 

The main route of elimination is via hepatic excretion into bile some enterohepatic recirculation may occur. The drug has a very low plasma clearance with negligible renal excretion. Neither amiodarone nor its metabolite is dialyzable. 

Excretion - The plasma half-life for trospium following oral administration is approximately 20 hours. After administration of oral trospium, the majority of the dose (85.2%) was recovered in feces and a smaller amount (5.8%) was recovered in urine 60% of the radioactivity excreted in urine was unchanged trospium. The mean renal clearance for trospium (29.07 L/h) is 4-fold higher than average glomerular filtration rate, indicating that active tubular secretion is a major route of elimination for trospium. There may be competition for elimination with other compounds that also are renally eliminated. 

Biliary excretion is the major route of elimination. Extended use at the recommended doses may cause accumulation of toxic amounts of dronabinol and its metabolites. 

Renal function Impairment The major route of elimination of unchanged topiramate and its metabolites is via the kidney. Dosage adjustment may be required. 

Pharmacokinetics Non-ergot dopamine agonists are rapidly absorbed. The absolute bioavailability is more than 90%. Steady-state concentrations are achieved within 2 days of dosing. Terminal half-life is about 8 hours (about 40 minutes for apomorphine) in young healthy volunteers and about 12 hours in elderly volunteers. Urinary excretion is the major route of elimination. 

Excretion - Fecal excretion was the major route of elimination following a single oral dose of 360 mg orlistat in healthy and obese subjects. Orlistat and... 

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