Urinary excretion model

This model accurately predicted the time curves for blood concentration and urinary excretion of metabolites by male volunteers exposed to 100 ppm trichloroethylene (Sato et al. 1991). It was found that, while the amount of metabolite excretion increases with body weight, the concentration does not, because of a corresponding increase in urinary volume. Also, women and obese people, compared with slim men, have lower concentrations but longer residence times of blood trichloroethylene because of their higher fat content (Sato et al. 1991). As a consequence, the model predicted that 16 hours after exposure to trichloroethylene, one could expect a woman s blood level to be 30% higher and an obese man s level to be twofold higher than that of a slim man (Sato 1993). 

Durbin and Schmidt (1985) proposed a model for tissue distribution and excretion of absorbed americium in humans. A unique feature of this model is that transfers from plasma to tissues are assumed to be instantaneous therefore, a central plasma (and blood) compartment is not included in the model (see Figure 3-10). Tissue compartments included in the model are slow and fast turnover bone compartments, representing cortical and trabecular bone, respectively liver and slow and fast turnover for other soft tissue compartments. Excretion pathways include urine and feces. Urinary excretion is represented as a sum of the contributions from bone, liver, and other soft tissues. Fecal americium is assumed to be excreted from the liver. 

Validation of the model. The Perbellini model was validated using a data set for venous blood /7-hexane values in volunteers exposed for 4 hours (Veulemans et al. 1982). The range in the study was 334-368 g/L during exposure to 204 ppm the model predicted a value within this range. After 4 hours exposure to 102 ppm, the predicted value for venous blood -hexane concentration was about 10% below that actually observed in humans. The authors also compared their own data from previous studies on the correlation between venous blood -hexane concentrations and workplace concentrations. From the correlation curve, exposure at 102 ppm would predict a venous blood concentration of 176 g/L the model predicted 182 g/L. The urinary excretion rate of 2,5-hexanedione predicted by the model was also compared to a data set from 13 workers followed for 24 hours from the beginning of a workday. 

The model successfully predicted the rate of 2,5-hexanedione urinary excretion. 

Manga, N., Dully, J.C., Rowe, P.H., and Cronin, M.T.D. A hierarchical QSAR model for urinary excretion of drugs in humans as a predictive tool for... 

Wang, J.M., Krudy, G., Xie, X.Q., Wu, C.D., Holland, G. Genetic algorithm-optimized QSPR models for bioavailability, protein binding, and urinary excretion. J. Chem. Inf. Model. 2006, 46, 2674-83. 

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. 

Figure 19.3 summarizes two major clearances governing the biodistribution of most macromolecular drugs—the hepatic uptake clearance and the urinary excretion clearance-of model compounds with diverse... 

The rate of absorption of 2,k,5-T into the body appeared to be slower after external exposure than after oral administration in humans. Pharmacokinetic modeling indicated 91% of the 2,h,5-T absorbed through the skin would be cleared within 1 week. Measurement of 2,k,5-T excreted in urine of spray crews demonstrated that the maximum absorbed dose is not likely to exceed 0.1 mg per kg of body weight per work day. Urinary excretion provided a more reliable measure of dose than analysis of patches worn by the workers. Exposure was highest in mixers who handled the spray concentrate and in sprayers using backpack equipment. 

Gargas et al. (1994) employed a three compartment model describing the urinary excretion of chromium (Aitio et al. 1988) to estimate the bioavailability of chromium(III) from chromium(in) picolinate in volunteers ingesting capsules containing 400 pg. The model contained 3 compartments, a fast-exchange compartment receiving 40% of absorbed chromium with a half-life of 7 hours, a medium-exchange... 

Graham, J.S., Reid, F.M. et al. (2000). A cutaneous full-thickness liquid sulfur mustard hum model in weanling swine clinical pathology and urinary excretion of thiodiglycol. J. Appl. Toxicol. 20 (Suppl. 1) S161-72. 

Urinary excretion data were used in a kinetic model to estimate the maximum uranium kidney concentrations of workers accidentally exposed to uranium hexafluoride (Fisher et al. 1990). Initial intakes of workers involved in the accident ranged from 470 to 24,000 pg uranium. The model estimated the maximum kidney concentrations in the workers as ranging from 0.048 to 2.5 pg U/g in kidney tissue renal toxicity was not observed in any of the workers (Fisher et al. 1990). 

Fisher et al. (1991) Biokinetic Model A modified biokinetic model for uranium was developed for inhaled soluble uranium based on human data from an accidental release of uranium hexafluoride in Oklahoma. Urinary excretion data from 31 exposed workers were used to test two previously published compartmental models for inhalation exposure to uranium (ICRP 1979 Wrenn et al. 1989). Urinary uranium was measured periodically for 2 years following the accident. Statistical analysis showed that the Wrenn et al. (1989) model produced a better fit to the excretion data than the ICRP (1979) model. 

The three major parameters examined in urinary excretion bioavailability studies are the cumulative amount of drug excreted unmetabolized in the urine ( Xu)-, the maximum urinary excretion rate (ERmax) and the time of maximum excretion rate (Tmax)- In simple pharmacokinetic models, the rate of appearance of drug in the urine is proportional to the concentration of drug in the systemic circulation. Thus, the values for Tmax and ERmax for urine studies are analogous to the Tmax and Cmax values derived from blood level studies. The value of r ax decreases as the absorption rate of the drug increases, and increases as the... 

An important question in the development and application of any new analytical procedure is what is the state of the art One aspect of the state of the art with respect to the determination of trace elements in urine is illustrated in Table I. The table shows the range of reported analytical values and the model values for 24-hour urinary excretion of a number of trace elements, as compiled from the report of the Task Group on Reference Man (6). The main feature of the information in Table I is that the range of reported normal values covers two orders of magnitude for most of the elements listed. There may be considerable variation in the normal excretion of trace elements in urine, but the extent of the ranges shown in the table also may be signiflcantly and artificially enhanced by wide variations in the accuracy of the analytical results that were surveyed. The latter view is supported by the data... 

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