Excretion pattern

The amount of each element required in daily dietary intake varies with the individual bioavailabihty of the mineral nutrient. BioavailabiUty depends both on body need as deterrnined by absorption and excretion patterns of the element and by general solubiUty, and on the absence of substances that may cause formation of iasoluble products, eg, calcium phosphate, Ca2(P0 2- some cases, additional requirements exist either for transport of substances or for uptake or binding. For example, calcium-binding proteias are iavolved ia calcium transport an intrinsic factor is needed for vitamin cobalt,... 

Biological characterization includes toxicological studies, dose relationships, routes of adininistration, identification of side effects, and absorption, distribution, metaboHsm, and excretion patterns. If the results are stiU acceptable, product formulation and dosage form are developed. The product should be pleasing to the patient and thus may contain flavoring and colorants. 

Phase I. This involves general testing for human pharmacology in healthy volunteers, ie, safe-dose adjustment deterrnination of absorption, metabohsm, and excretion patterns and monitoring for side effects. Usually fewer than 10 test subjects ate involved. 

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. 

The duration of collection of biological samples from farm workers is determined by the excretion pattern of the active ingredient or its metabolites. Generally, collection will encompass a period of time prior to exposure to about 1-3 days beyond exposure. Background samples should be taken from workers for the 24 h prior to the first application of the test product. This will allow an up-to-date examination of the background levels of the parent or metabolites in the worker s urine. 

The sample size for any biological sample depends on two criteria (1) the amount of sample needed by the analytical laboratory and (2) the portion of the excretion pattern that the researcher is interested in observing. 

Another option for the researcher is to collect two 12-h urine samples each in 4-L polyethylene urine collection vessels or in large 1-L wide-mouthed polyethylene jars. This allows the researcher to examine the excretion pattern of the active ingredient in two 12-h segments. 

Since collection of all urine from volunteers over a 24-h period may not be possible, creatinine analysis of the composite total urine sample is recommended. This will allow for a more scientific analysis and interpretation of the excretion pattern presented by the worker during the course of the monitoring. 

Whichever technique is used, it is recommended that urine samples from volunteers be taken for an extended period of time that encompasses the entire post-exposure excretion of the active ingredient or its metabolites. In addition, it is recommended that the study volunteer refrain from handling the active ingredient for an extended period after the application phase or re-entry phase of the study is completed and until the collection of urine samples is completed. This will allow for the excretion pattern of the active ingredient or metabolites to achieve a profile that is more easily interpreted by the investigator. 

Whereas the use of laboratory animals is of great value in determining the metabolism and excretion patterns of the pesticide in question, this technique can have some drawbacks, especially if the human metabolism and excretion patterns are different from those for laboratory animals for the pesticide. If no human metabolism and excretion data are available, one must be careful with the interpretation of the urine data from the workers. 

Approximately 80% of administered radioactivity was excreted in the feces of rats within 2 days of oral administration of single 0.66 mL/kg doses of tritiated mineral oil (Ebert et al. 1966). Of administered radioactivity, 7-8% was excreted in the urine, but was in chemical forms other than mineral oil. The fecal radioactivity was predominately (90%) in the form of mineral oil. Pretreatment of the rats with 0.66 mL/kg/day nonradioactive mineral oil for 31 days did not substantially alter the excretion patterns. 

Urinary excretion patterns of thiocyanate suggest that there are quantitative species differences in acrylonitrile metabolism (Ahmed and Patel 1981). Thiocyanate was identified as a metabolite in rats, mice, rabbits and Chinese hamsters. About 20 to 23% of the administered dose was excreted as thiocyanate in rats, rabbits and Chinese hamsters, while 35% was excreted as thiocyanate in mice (Gut et al. 1975). It has also been observed that mice metabolize acrylonitrile more rapidly than rats (Ahmed and Patel 1981 Gut et al. 1975). Maximum blood cyanide concentrations were observed 1 hour after dosing in mice, but 3 hours after dosing in rats (Ahmed and Patel 1981). In mice, thiocyanate was present in the urine within 4 hours of dosing, while in rats, thiocyanate was present in urine only at time intervals longer than 4 hours (Gut et al. 1975). 

The table below shows the urinary excretion patterns of electrolytes of diuretic drugs. For each of the diuretic agents listed below, choose the urinary excretion pattern that the drug would produce. 

The answers are 373-d, 374-c, 375-a. (Kut ung, pp 253— 254, 256-257.) The urinary excretion pattern of electrolytes for the thiazide diuretic agents (e.g., hydrochlorothiazide) shown in the table that accompanies the question is represented by choice a. These drugs block the reabsorption of Na and Cl at the early distal convoluted tubule of the nephron. In addition, they promote the excretion of K and Mg. At high doses, the thiazide diuretics (especially hydrochlorothiazide) may cause a... 

Excretion patterns for Cr+3 in rats were unpredictable and difficult to calculate (Yamaguchi et al. 1983). The excretion patterns for fecal chromium among 40 grazing Angus cows given 20 g dietary Cr203 (13.6 g Cr+3) daily for 72 days was diurnal excretion was lowest at 8 p.m. and highest at 9 a.m. (Hopper et al. 1978). 

Hopper, J.T., J.W. Holloway, and W.T. Butts, Jr. 1978. Animal variation in chromium sesquioxide excretion patterns of grazing cows. Jour. Anim. Sci. 46 1096-1102. 

Hendriks, W.H., Tarttelin, M.F. and Moughan, P.J. (1995c) Twenty-four hour felinine excretion patterns in entire and castrated cats. Physiol. Behav. 58, 467-469. 

Species Differences. Species differences in metabolism are amongst the principal reasons that there are species differences in toxicity. Differences in cytochrome P450 is one of the most common reasons for differences in metabolism. For example, Monostory et al. (1997) recently published a paper comparing the metabolism of panomifene (a tamoxifen analog) in four different species. These data serve to address that the rates of metabolism in the non-human species was most rapid in the dog and slowest in the mouse. Thus, one should not a priori make any assumptions about which species will have the more rapid metabolism. Of the seven metabolites, only one was produced in all four species. Both the rat and the dog produced the two metabolites (M5 and M6) produced by human microsomes. So how does one decide which species best represents humans One needs to consider the chemical structure of the metabolites and the rates at which they are produced. In this particular case, M5 and M6 were relatively minor metabolites in the dog, which produced three other metabolites in larger proportion. The rat produced the same metabolites at a higher proportion, with fewer other metabolites than the dog. Thus, in this particular instance, the rat, rather than the dog, was a better model. Table 18.8 offers a comparison of excretion patterns between three species for a simple inorganic compound. 

On the basis of the high degree of individuality of excretion patterns demonstrated in our laboratoriesl as well as the genetic considerations set forth in Chapter II, it appears probable that individuality in composition exists. The brain, blood, bones, muscles, and glands are probably distinctive for each individual not only in anatomy but also in chemical composition. This does not mean, of course, that... 

Most conclusive evidence of the biochemical individuality of every human specimennot restricted to those who exhibit marked idiosyncrasieshas been obtained by the recent studies of urinary excretion patterns using paper chromatography and other methods.2,3,4 Typical results from one study2 illustrating how various items in the patterns vary from individual to individual are shown in Figure 13. 

Similar extended studies from the Institute for the Study of Human Variation at Columbia University involving twins indicate that genetic factors are operative in the control of the excretion of certain amino acids.5,6 Sutton and Vandenberg4 have also studied variation in human excretion patterns. 

Urinary excretion patterns of six individuals. Gu = glucose C = creatine ... 

The twin variance studies cited above5,6 indicate that dietary differences are not primarily responsible for the differences in the urinary excretion patterns. Additional evidence is of several sorts. Two experiments,8,9 each involving placing individuals on uniform diets, have... 

These findings show clearly that even when the animal diets are uniform, highly distinctive urinary excretion patterns are exhibited. The results with different inbred strains show that inheritance is the basic reason for the differences in pattern. It would require extremely extensive genetic studies to demonstrate the inheritance process for each item, but this does not seem crucially important from the standpoint of elucidating the phenomenon of individuality. 

Excretion patterns of individual rats. Vertical bars represent the ratio of the average excretion of urinary constituents (expressed as mg. constituent per mg. creatinine) for individual rats divided by average excretion for the group. 

Excretion patterns of rats of different strains. Vertical bars represent the ratios of average excretions of urinary constituents (expressed as mg. constituent per mg. creatinine) by the rats in each strain divided by the average excretion for the rats in all strains. Broken line indicates average excretion for all strains. Cr = creatinine P = phosphorus As = aspartic acid G1 = glutamic acid T = taurine ... 

With respect to amino acid excretion Woodson and co-workersl3 and othersl4,15 have found by microbiological methods large variations. Stein 16 obtained evidence of wide variations in the amino acid excretion of cystinurics. Further data are also available with respect to creatine and creatinine excretion which bear out our conclusion regarding individuality of excretion patterns. 17,18,19... 

The existence of excretion patterns is apparently not limited to urine. In a recent study it was found that normal individuals on constant dietary intakes excreted a characteristic percentage of the nitrogen in the feces. In successive years, one individual excreted in the feces 7.02 and 7.89 per cent, respectively, of the nitrogen consumed. In another individual the percentages were 8.72 and 10.02 per cent in still another, 8.52 and 8.93 per cent and in a fourth, 13.0 per cent (1 year only).34... 

The fact that amino acid excretion patterns (p. 111), amino acid salivary patterns (p. 65), and amino acid duodenal juice patterns (p. 68) are distinctive for each individual is in line with the idea of distinctive needs. That there are wide ranges (presumably distinctive for each individual) in the content of blood plasma (p. 60) with respect to individual amino acid points in the same direction. 

The fact that each inbred strain of animals has not only a distinctive tendency to drink alcohol but also a distinctive excretion pattern makes it seem certain that we are here dealing with individual differences (quantitatively speaking) in nutritional needs. It seems evident that when rats are given plenty of everything they need nutritionally they shun alcohol, and that the reason why some shun it less than others is that their requirements for certain items are higher, and they... 

The genetotrophic idea was first conceived in connection with the experimental work on alcohol consumption by rats. When it was found that the alcohol consumption of rats (1) was highly individual 12, 13, 14 (as were also their excretion patterns), 15 and (2) was genetically controlled (as evidenced by the distinctive behavior of each inbred strain and the relatively small variation within inbred strains),13, 14 and (3) could be increased by deficient diets and abolished by fortified ones, 12, 13 the genetotrophic ideas appeared to be the only reasonable interpretation of the facts. 16,17 Since these original observations were made, dozens of other facts, many of which have been and will be presented in the present volume, have become explicable on the basis of the genetotrophic concept. To date there are no observations, so far as I am aware, that appear to go counter to this idea. 

Even among members of highly inbred strains of rats (brother-sister mated for as long as 50 generations) we have found substantial intrastrain differences in excretion patterns and alcohol-consuming tendencies 18 therefore, it is not surprising that within the strains of... 

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