Urinary excretion physiology

As blood moves through the kidneys, chemicals and their metabolites can be filtered out or otherwise lost from the blood by a set of extraordinary physiological mechanisms that release them into urine. Urinary excretion is probably the pathway out of the body for most chemicals. 

Gaigas et al. (1995) have developed a physiological toxicokinetic model of acrylonitrile in rats which includes the behaviour of CEO. In-vitro kinetic studies of the metabolism of both acrylonitrile and CEO showed that epoxidation to CEO is saturable, while glutathione conjugation of acrylonitrile follows first-order kinetics. The model combines these kinetic parameters with tissue partition data to allow simulation of the urinary excretion of acrylonitrile metabolites and the fonnation of haemoglobin adducts (see below). The model has been further refined by Kedderis et al. (1996) to predict the behaviour of acrylonitrile and CEO after inhalation exposure to acrylonitrile. 

Csanaky, I. and Gregus, Z. (2002) Species variations in the biliary and urinary excretion of arsenate, arsenite and their metabolites. Comparative Biochemistry and Physiology C-Toxicology and Pharmacology, 131(3), 355-65. 

The other approach is indirect, namely, to measure not enzymes as such, but their physiological biochemical efficacy. This can be achieved by oral administration of a composite test substance, which is hydrolyzed ( digested ) into its components exclusively by a specific pancreatic enzyme and subsequently absorbed and eliminated by the renal or the respiratory system. Ideally, the urinary excretion/respiratory exhalation of a metabolite of the test substance is proportional to its hydrolysis in the small intestine, which in turn is directly dependent on the quantity of pancreatic enzymes present. 

Urinary excretion of the radiolabel was greatest in the first two hours following skin application. More than 80% of the total excretion occurred in the first 8 hours. In another study, 35-43 cm2 of the forearm were exposed to approximately 0.06 g/cm2 of liquid benzene for 1.25-2 hours (Hanke et al. 1961). The absorption was estimated from the amount of phenol eliminated in the urine. The absorption rate of liquid benzene by the skin (under the conditions of complete saturation) was calculated to be low, approximately 0.4 mg/cm2/hour. The absorption due to vapors in the same experiment was negligible. Although there was a large variability in the physiological values, the amount of excreted phenol was 8.0-14.7 mg during the 24-hour period after exposure. It is estimated that approximately 30% of dermally absorbed benzene is eliminated in the form of phenol in the urine. 

The principal physiological role of vitamin D is in the maintenance of the plasma concentration of calcium. Calcitriol acts to increase intestinal absorption of calcium, to reduce its excretion by increasing reabsorption in the distal renal tubule, and to mobilize the mineral from bone - of the 25 mol of calcium in the adult body, 99% is in bone. The daily intake of calcium is around 25 mmol, and intestinal secretions add an additional 7 mmol to the intestinal contents 10 to 14 mmol of this is normally absorbed, with 18 to 22 mmol excreted in feces. Bone turnover accounts for exchange of 10 mmol of calcium between bone and plasma daily. The kidneys filter some 240 mmol of calcium daily, almost all of which is reabsorbed urinary excretion of calcium is about 3 to 7 mmol per day. 

There are examples of weak acids reabsorbed by simple nonionic diffusion which urinary excretion is not influenced by changes in urine pH. It is the case if the pKa is above or close to the upper limit of urine pH, as it is the case for barbital (pKa = 7.8), and a few other barbiturates. Also, if the pKa value is very low, such as it is the case for 2-nitroprobenecid (pKa=1.3), the acid remains mainly unionized in the physiological range of urine pH [15], and its excretion remains independent of fubular urine pH. 

The third interleukin family is the IL-17 family. Interleukin-17 is a pro-inflamatory cytokine that is primarily secreted from T-lymphocytes and whose physiological significance is only just beginning to be determined [241, 242]. Increased urinary excretion of interleukin-17 has been found in nephrotic patients [243]. 

The Physiological Basis of Veterinary Clinical Pharmacology Table 6.3 Half-life and urinary excretion of trimethoprim. 

PRITCHARD, J.B. and JAMES, M.O. (1982) Metabolism and urinary excretion. In Metabolic Basis of Detoxication, edited by W.B.Jakoby, J.R.Bend and J.Caldwell (New York Academic Press). PRITCHARD, J.B. and MILLAR, D.S. (1993) Mechanisms mediating renal secretion of organic anions and cations. Physiolog. Rev., 73, 765-796. SMITH, R.L. (1973) The Excretory Function of Bile (London Chapman Hall). 

Thiazide diuretics, typified by hydrochlorothiazide, tend to cause excess urinary excretion of potassium over sodium ion, upsetting the normal semm concentration of these ions. Administration of spirobutyrolactones, on the other hand, leads to a more physiological balance of those ions in urine. As a result, these dmgs are often termed potassium-sparing diuretics. The pioneer orally active spirobutyrolactone (37-2) is still on the market as a diuretic under the generic name spironolactone and the trade name Aldactone. Now that the patent has expired, the agent is now sold as a generic dmg by many manufacturers, and as a result is available under a plethora of trade names. 

Trivalent chromium is the most stable form in the food supply. Absorption estimates for chromium(III), based on metabolic balance studies or on urinary excretion from physiological intakes, range from 0.4 to 2.5% (Doisy et al. 1971 Bunker et al. 1984 Anderson and Kozlovsky 1985 Offenbacher etal. 1986 Anderson 1987). Because of analytical problems associated with the measurement of chromium absorption, several investigators have used the urinary excretion of chromium as an indicator of absorption. When dietary chromium intake was 10 pg per day, 2% of that amount was absorbed (estimated as urinary excretion), whereas at a chromium intake of 40 pg only 0.4-0.5% of the chromium was recovered in the urine (Anderson and Kozlovsky 1985). 

Experimental data never fit the model precisely. Often a variety of parameter estimates may give similarly good fits to the model and some of the predicted characteristics may be inconsistent with the physiological observations (Cobum et al., 1985). In the two-pool model used by Johansson et al., the urinary excretion of isotope after a single bolus will follow an equation of the general form... 

A study in healthy subjects found that the absorption of a single 500-mg dose of ascorbic acid was about one-third lower in those given aspirin 900 mg eoncurrently, and the urinary excretion was about 50% lower. The elinieal importance of this is uneertain. It has been suggested that the normal physiological requirement of 30 to 60 mg of ascorbic acid daily may need to be increased to 100 to 200 mg daily in the presence of aspirin. Another study in 9 healthy subjeets found that ascorbic acid 1 g three times daily did not significantly affect serum salieylate levels of choline salicylate. ... 

Frequently, the reason for the failure of a worker exposure experiment Is the lack of basic Information on relevant human biochemistry and physiology. A thorough literature search for Information on the urinary excretion kinetics, etc. of the compound under Investigation could be a very worthwhile prior Investment. 

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