Rate of excretion

Pharmacokinetic studies are designed to measure quantitatively the rate of uptake and metaboHsm of a material and determine the absorbed dose to determine the distribution of absorbed material and its metaboHtes among body fluids and tissues, and their rate of accumulation and efflux from the tissues and body fluids to determine the routes and relative rates of excretion of test material and metaboHtes and to determine the potential for binding to macromolecular and ceUular stmctures. 

Older adults are at increased risk for toxicity because of a decreased rate of excretion, bower dosages may be necessary to decrease the risk of toxicity. 

The body maintains blood pH by two primary mechanisms respiration and excretion. Carbonic acid concentration is controlled by respiration as we exhale, we deplete our system of CO, and hence deplete it of H2C03, too. This decrease in acid concentration raises the blood pH. Breathing faster and more deeply increases the amount of C02 exhaled and hence decreases the carbonic acid concentration in the blood, which in turn raises the blood pH. Hydrogen carbonate ion concentration is controlled by its rate of excretion in urine. 

Excretion of the drug and/or its metabolites takes place primarily in the kidney, though some drugs also show considerable excretion via the bile/faeces. Again, it is important to study the rates of excretion of the drug or its metabolites, and to verify that there is no associated kidney damage. 

In another study (Gage and Holm 1976), the influence of molecular structure was studied on the rate of excretion by mice for 14 different congeners. The results were as follows ... 

Chipman, J.K. and Walker, C.H. (1979). The metabolism of dieldrin and two of its analogues the relationship between rates of microsomal metabolism and rates of excretion of metabolites in the male rat. Biochemal Pharmacology 28, 1337-1345. 

The release of steroids such as progesterone from films of PCL and its copolymers with lactic acid has been shown to be rapid (Fig. 10) and to exhibit the expected (time)l/2 kinetics when corrected for the contribution of an aqueous boundary layer (68). The kinetics were consistent with phase separation of the steroid in the polymer and a Fickian diffusion process. The release rates, reflecting the permeability coefficient, depended on the method of film preparation and were greater with compression molded films than solution cast films. In vivo release rates from films implanted in rabbits was very rapid, being essentially identical to the rate of excretion of a bolus injection of progesterone, i. e., the rate of excretion rather than the rate of release from the polymer was rate determining. 

PBPK models have also been used to explain the rate of excretion of inhaled trichloroethylene and its major metabolites (Bogen 1988 Fisher et al. 1989, 1990, 1991 Ikeda et al. 1972 Ramsey and Anderson 1984 Sato et al. 1977). One model was based on the results of trichloroethylene inhalation studies using volunteers who inhaled 100 ppm trichloroethylene for 4 horns (Sato et al. 1977). The model used first-order kinetics to describe the major metabolic pathways for trichloroethylene in vessel-rich tissues (brain, liver, kidney), low perfused muscle tissue, and poorly perfused fat tissue and assumed that the compartments were at equilibrium. A value of 104 L/hour for whole-body metabolic clearance of trichloroethylene was predicted. Another PBPK model was developed to fit human metabolism data to urinary metabolites measured in chronically exposed workers (Bogen 1988). This model assumed that pulmonary uptake is continuous, so that the alveolar concentration is in equilibrium with that in the blood and all tissue compartments, and was an expansion of a model developed to predict the behavior of styrene (another volatile organic compound) in four tissue groups (Ramsey and Andersen 1984). 

Urine is the principal excretory route for elimination of diisopropyl methylphosphonate after oral administration to mice, rats, pigs, mink, or dogs (Hart 1976 Snodgrass and Metker 1992 Weiss et al. 1994). However, the rate of excretion differs among species. Peak urinary excretion of a single oral dose of 225 mg/kg [14C]-radiolabeled diisopropyl methylphosphonate occurred at 6 hours in mice,... 

In rats given 66 or 660 mg/kg diisopropyl methylphosphonate, peak radioactivity in the blood was at 2-3 hours in both sexes at both doses however, radioactivity was still detectable in the blood 24 hours postadministration in the 66-mg/kg group (Weiss et al. 1994). After intravenous administration of 66 mg/kg, the elimination half-life of diisopropyl methylphosphonate was estimated at 45 minutes in males and 250 minutes in females the rate of excretion was greater in males than in females. Urine and feces together accounted for 86-97% of administered radioactivity in males and 57-62% in females. 

A small part of divalent mercury is reduced to mercury vapour. This reduction probably accounts for the ability of certain commonly occurring microorganisms to volatilize mercury for biological media [59]. Loss of volatile radioactive mercury was observed in rats injected with salts of divalent mercury labelled with the 203Hg isotope [60]. Part of the volatile mercury was exhaled via the lungs, the remainder by way of the skin and fur. The volatile loss accounted for up to 20% of the total rate of excretion of mercury from the animals. 

Once the SWNTs were delivered to the tumor, they could be heated by laser irradiation to destroy the tumor. This group also noted that they did not observe any obvious toxicity in the mice when injected with SWNTs up to dosages of 2 mg/kg. However, they found that the rate of excretion of SWNTs was very low. Thus, longterm studies are needed to investigate toxicity issues (Liu et al., 2007). 

A plot of rate of transport against solute concentration in the tubule (Figure 8.3) shows fm, the tubular transport maximum to be analogous with Vmax for an enzyme, which is a maximum rate of solute transport across tubular cells. Assuming a fixed GFR, the point at which the plotted line begins to deviate from linearity, indicates that the substance exceeds a critical threshold concentration and begins to be excreted in the urine. When the plotted line reaches a plateau indicating that saturation point, that is tm has been reached, the rate of excretion is linear with increase in plasma concentration. The concept of fm as described here for tubular reabsorption applies equally well to carrier-mediated secretory processes. If the fm value for a particular is exceeded for any reason, there will be excretion of that solute in the urine. 

Slow poisoning can occur in several different ways. In some cases, chemicals or their metabolites may slowly accumulate in the body -rates of excretion are lower than rates of absorption - until tissue and blood concentrations become sufficiently high to cause injury. Delayed toxicity can also be brought about by chemicals that do not accumulate in the body, but which act by causing some small amount of damage with each visit. Eventually, these small events, which usually involve... 

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). 

Kirk GJD, Santos EE, Santos MB. 1999. Phosphate solubilization by organic anion excretion from rice growing in aerobic soil rates of excretion and decomposition, effects on... 

The second thing that happens is a very good thing. The liver upregulates its LDL receptor level. In snm, the liver does the two things that it can do to maintain an adequate source of its cholesterol pump up the synthesis (to normal or slightly subnormal rates only) and pnmp np the seqnestration of cholesterol from the blood LDLs. The net effect is that the rate of excretion of cholesterol from the body is increased due to the increase in the nnmber of LDL receptors expressed on hepatic cells without compromising the availability of cholesterol to meet cellular needs. 

The formation and excretion of urea is the primary mechanism by which excess nitrogen, in the form of ammonia, is removed from the body. Surprisingly, it was found that the actual rate of urea synthesis exceeded considerably the rate of excretion of the urea. The interesting question, therefore, is what is the fate of this lost urea The answer is that urea enters the large intestine, where it is degraded by microorganisms that possess the enzyme urease, which catalyses the reaction ... 

During intoxication, there is a striking elevation of the rate of excretion of lead in the urine, but only a negligible or slight elevation of the concentration of lead in the blood. In severe intoxication, the urine lead is rarely less than 350p,g/l of urine, whereas the blood... 

Elderly The decreased rate of excretion in the elderly contributes to a high incidence of toxic effects. Use lower doses and more frequent monitoring. 

The disposition patterns of psoralen and Isopsoralen in polyxenes under the parameters studied were not dramatically different. As Indicated in Table III, there were no appreciable differences in the rate of excretion of radioactivity by caterpillars treated with the two compounds. In body tissues, however, levels of total radioactivity in Isopsoralen-treated caterpillars were consistently about twice those observed in psoralen-treated insects (Table IV). Further, levels of unmetabolized parent compounds retained in body tissues (where toxic effects would be expressed) were on the order of 3 times as high in caterpillars treated with the angular furanocoumarin, isopsoralen (Table V). 

Seventy-four percent of oral doses of PCMTB-l C were excreted in the bile by conventional rats. Most of this (50 to 70%) has been characterized to be products of the MAP (8). Neither of the mercapturates shown in fig. 3 were secreted in the bile therefore, the mercapturic acids that were excreted with the germfree rat feces had to have been formed either by metabolism of the precursors of the mercapturic acid by the intestinal mucosa, or by the tissues during enterohepatic circulation of these precursors. Comparison of the rates of excretion of oral doses of PCMTB- C given to germfree and conventional rats indicate that there was enterohepatic circulation of the in the germfree rats. Conventional rats excreted more than 80 percent of the dose in the feces within two days while it took at least eight days for the germfree rats to excrete 80 percent of the dose in the feces. 

Little quantitative information was located regarding the amount or fraction of absorbed carbon tetrachloride that is subsequently excreted in air, urine or feces in humans exposed by inhalation. Studies of the rate of excretion of carbon tetrachloride in the expired air was conducted in a worker who had been exposed of carbon tetrachloride vapors for several minutes (Stewart et al. 1965). 

Biomarkers of Exposure and Effect. The presence of carbon tetrachloride in expired air is the most commonly used biomarker of exposure. The rate of excretion in humans appear to be biphasic, with an initial elimination half-life of less than 1 hour, and a second phase of about 30-40 hours. The compound can be detected in expired air within hours to weeks after exposure. Research on additional biomarkers of exposure would be of value, perhaps in areas such as detection of DNA adducts by P- postlabelling or immunological methodologies. 

Pharmacokinetics Phenylephrine is irregularly absorbed from and readily metabolized in the GI tract. After IV administration, a pressor effect occurs almost immediately and persists for 15-20 minutes. After IM administration, a pressor effect occurs within 10-15 minutes and persists for 50 minutes to 1 hour. After oral inhalation of phenylephrine in combination with isoproterenol, pulmonary effects occur within a few minutes and persist for about 3 hours. The pharmacologic effects of phenylephrine are terminated at least partially bythe uptake of the drug into the tissues. Phenylephrine is metabolized in the liver and intestine by the enzyme monoamine oxidase (MAO). The metabolites and their route and rate of excretion have not been identified. 

In contrast to penetrating radiation, which passes through tissue in a weU-known manner, or even with the more complex situations arising fiom nonuniform distributions of internally deposited radionuclides, dosimetry of chemicals is far more difficult. Factors requiring consider ation in chemical dosimetry include the type of chemical under consideration, dose, duration of exposure, route of administration, aU possible metabolic pathways, capacity of the chemical to affect its own metabolism, pharmacokinetics, rate of excretion, and dose to the biological target at sites of tumor formation (which may vary depending on the route of administration). 

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