Prediction tissue levels

Demchuk AM, Morgenstem LB, Krieger DW, Linda Chi T, Hu W, Wein TH, Hardy RJ, Grotta JC, Buchan AM. Serum glucose level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke. Stroke 1999 30(l) 34-39. 

Toxicokinetics studies are designed to measure the amount and rate of the absorption, distribution, metabolism, and excretion of a xenobiotic. These data are used to construct predictive mathematical models so that the distribution and excretion of other doses can be simulated. Such studies are carried out using radiolabeled compounds to facilitate measurement and total recovery of the administered dose. This can be done entirely in vivo by measuring levels in blood, expired air, feces, and urine these procedures can be done relatively noninvasively and continuously in the same animal. Tissue levels can be measured by sequential killing and analysis of organ levels. It is important to measure not only the compound administered but also its metabolites, because simple radioactivity counting does not differentiate among them. 

Biomarkers of Exposure and Effect. Although tin and its compounds can be measured in tissues, blood, urine, and feces, it is difficult to quantitatively predict exposure levels from such determinations. 

Target tissues. Tissue levels of chromium(ni) and chromium(VI) in the rat lung, erythrocyte, liver, and kidney can be predicted by this model. 

Estimates of human exposure to JP-8 do not provide documentation of exposures to individual components of JP-8. Studies have not been done to determine which components of JP-8 might account for its toxicity. Thus, the value of calculation of a margin of exposure for JP-8 is questionable because knowledge of the composition of JP-8 might not accurately predict the relative exposure to components of JP-8 at the tissue level. 

Present-day risk assessment methodologies have an increasing emphasis on physiologically based pharmacokinetics (PBPK) or toxicokinetic models and mode of action (MOA). Snch models have been developed to predict exposure levels in target tissues for a large number of agents. PBPK models are especially useful in the risk assessment context because they allow data to be extrapolated across species, dose levels, and routes of exposure. 

This compound caused bladder cancer in experimental animals when these were exposed to levels of 5-7% of the diet but not if exposed to levels up to 5%. However, pharmacokinetic studies revealed that at these high exposure levels the plasma clearance of saccharin was saturated and therefore tissue levels would be higher than expected on the basis of a linear extrapolation from lower doses. Consequently, prediction of the incidence of bladder tumours at the lower exposure levels to which humans would be... 

Disposition and Pharmacokinetics Azathioprine is well absorbed orally and reaches maximum blood levels within 1-2 hours after administration. The tj of azathioprine is 10 minutes, while that of its metabohte 6-mercaptopurine is about an hour. Blood levels have limited predictive value because of extensive metabolism, significant activity of many different metabolites, and high tissue levels attained. Azathioprine and mercaptopurine are moderately bound to plasma proteins and are partially dialyzable. Both are rapidly removed from the blood by oxidation or methylation in the liver and/or erythrocytes. Renal clearance has little impact on biological effectiveness or toxicity, but the dose should be reduced in patients with renal failure. 

Biomarkers are objective indicators of particular pathogenic processes, pharmacological responses, or normal biological states they can involve any kind of molecule in living organs, for example, proteins, peptides, DNA, and/or metabolites. Biomarkers are essential for the diagnosis and prediction of diseases IMS can provide distribution information regarding various biomolecules at the cell and tissue levels, and thus it is expected to become a powerful tool for in situ biomarker discovery. 

It is recommended that LD q be determined in mice and rats, and MTD be determined in dogs and monkeys. Drug disposition studies and plasma level determinations should be performed in these species after parenteral administration of the LDio, half the LDiq, and one-tenth the LD o. The area under the serum curve for the various doses should bear a linear relationship to the dose in mg/m or to the dose in mg/kg x If these relationships hold for the different laboratory species, they are likely to hold for man. If reasonably linear relationships do not obtain, it suggests that unique metabolic pathways may exist in some species, or that the enzymatic process may have been overwhelmed by virtue of high tissue levels of the drug [23]. Stated in another way, if one sees great variations in the response of experimental animals that bear no relationship to the size of the animals, then it is unlikely that any prediction can be made for man. On the other hand, where these relationships can be established, it seems possible that an inter-species dose-response phenomena intimately tied to plasma levels can be constructed. 

Weiner et al. (2009) identified the pyrethroids by CAS no. in his FOB smdies. Absolute stereochemistry was indicated for deltamethrin, S-Bioallethrin, esfenvalerate, (X-cyhalothrin), and relative stereochemistry for bifenthrin and tefluthrin. Stereochemistry was not divulged for p-cyfluthrin, cypermethrin, permethrin, resmethrin, fenpropathrin, and the pyrethrins. Dosages, body weights, and time to peak effect provide useful information for setting oral exposure levels (gavage) and comparing peak effect times with predicted tissues concentrations from PBPK/PD models. 

The failure of the artificially high titers of JHE to disrupt larval development may be due to several factors. Since the reduction in JHE is mediated by a variety of events, one can predict that for recombinant JHE to be effective, levels in the hemolymph must greatly exceed those normally present in the last larval instar. In normal larvae JH metabolism by esterase and epoxide hydrolase is high in most tissues while in infected larvae JHE levels increase in the hemolymph and infected, but presumably not uninfected tissues. Thus tissue levels of JH may not decrease sufficiently to induce metamorphosis. Since epoxide hydrolase levels are not affected there is also the possibility that JH acid may be remethylated to an active form in some tissues. The JH binding protein is hypothesized to increase the degradation of JH in the presence of JHE by keeping the JH in a pool accessible to the enzyme. However, the titers of JH binding protein in infected insects are not known. 

Hydrofluoric Acid Reactivity with Bone. Students are presented with an exposure story regarding hydrofluoric acid. A description of skin absorption, lack of burning sensation and bone composition (calcium carbonate) is provided. Students are then asked to balance a simple neutralization reaction between the acid and the bone suing proper nomenclature and stoichiometry. Discussion of why hydrofluoric is not rated as corrosive is facilitated, as well as a prediction of what will happen at the tissue level (bone) when this exposure occurs. MSDSs are a good source of reactivity information for this exercise. 

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