Absorption, distribution, metabolism species differences

Comparative Toxicokinetics. The absorption, distribution, metabolism, and excretion of acrylonitrile in rats has been studied. Limited work in other species suggests that important species differences do exist. Further evaluation of these differences, and comparison of metabolic patterns in humans with those of animals would assist in determining the most appropriate animal species for evaluating the hazard and risk of human exposure to acrylonitrile. 

If animals or humans are exposed to pharmaceutical compounds, they will either elicit a pharmacodynamic effect, e.g., show a suppression of blood pressure, or reveal in analytical blood samples exposure levels of the compound. This kinetic information of the parent compound and its metabolites is an important contribution for the extrapolation of safety data from animal studies to humans. Species differ considerably in regard to their kinetic conditions as Cmax, Tmax, Area Under the Curve (AUC), im and ADME (Absorption, Distribution, Metabolism and Excretion). 

The absorption, distribution, metabolism, and excretion in the species used in the toxicology studies should be discussed. Quantitative or notable qualitative differences in ADME between the various animal species and humans should be discussed, as well as any references to observed species differences in toxicity and extrapolation of the findings to humans. The significance of these findings to the interpretation of the results of the carcinogenicity, bioassay, and other preclinical toxicity studies should be considered. 

Comparative Toxicokinetics. Qualitatively, absorption, distribution, metabolism, and excretion appear to be similar in humans and laboratory animals. However, quantitative variations in the absorption, distribution, metabolism, and excretion of benzene have been observed with respect to exposure routes, sex, nutritional status, and species. Further studies that focus on these differences and their implications for human health would be useful. Additionally, in vitro studies using human tissue and further research into PBPK modeling in animals would contribute significantly to the understanding of the kinetics of benzene and would aid in the development of pharmacokinetic models of exposure in humans. These topics are being addressed in ongoing studies (see Section 2.10.3). 

Renwick examined the nature of the UFs generally applied for intraspecies and interspecies extrapolations. He proposed the division of each of these UFs into subfactors to allow for separate evaluations of differences in toxicokinetics and toxicodynamics. The toxicokinetic considerations include absorption, distribution, metabolism, and excretion of a toxic compound, and therefore address differences in the amount of the parent compound or active metabolite available to the target organ(s). The toxicodynamic considerations are based on variations in the inherent sensitivity of a species or individual to chemical-induced toxicity, and may result from differences in host factors that influence the toxic response of a target organ to a specified dose. The advantage to such a subdivision is that components of these UFs... 

How can late-stage clinical attrition be reduced and yet still produce a safe and efficacious drug This is the number one question that every member of the biophar-maceutical industry is trying to answer. Reducing early-stage clinical attrition is a difficult task because animal models are not perfect predictors of efficacy and safety in humans [8], Many factors can confound the safety and efficacy predictions used to move a new chemical entity (NCE) into the clinic, among them absorption, distribution, metabolism, and excretion (ADME) properties and the mechanism of toxicity differences between the preclinical species and humans. 

Comparative Toxicokinetics. The available information indicates that the absorption, distribution, metabolism, and excretion of creosote is qualitatively similar in humans and rodents. This general conclusion was primarily based on evidence derived from studies on the individual PAH components of creosote. Recent papers have described specific kinetic aspects of individual components of the coal tar products. Little work has been done to address this topic for wood creosote. Detailed pharmacokinetic studies in humans and animals specific to the creosote mixture would provide a better indication of species differences and indicate whether the ability to extrapolate across species may be possible in the future. 

A compound s action or effect within the body over a period of time is regulated by pharmacokinetics absorption, distribution, metabolism, and elimination, These processes differ across species and provide some insight into species variability following exposure to anti-ChEs, In addition to species-dependent effects, signs and symptoms of ChE inhibition by OPs or CMs depend on the compound, dose, route, frequency and duration of exposure, as well as the time of observation relative to the time of peak effect (Table 1). Therefore, it is difficult to compare species across studies in which any one of these factors is not consistent, and the reader must bear this in mind when reviewing the literature for species-related differences. 

The absorption, distribution, metabolism and excretion of ochratoxin A have been summarized previously by the Committee as follows (Annex 1, reference 153). Ochratoxin A is efficiently absorbed from the gastrointestinal tract, mainly in the small intestine. Information from a number of species shows that it is distributed via the blood, mainly to the kidneys, with lower concentrations being found in liver, muscle and fat. Transfer to milk has been demonstrated in rats, rabbits and humans, but little is transferred to the milk of ruminants, owing to hydrolysis of ochratoxin A into phenylalanine and ochratoxin alpha by the rumenal microflora. The major metabolite of ochratoxin A in all species examined is ochratoxin alpha, formed by hydrolysis of the peptide bond. Ochratoxin alpha and minor hydroxylated metabolites that have been identified are all reported to be less toxic than ochratoxin A itself. Ochratoxin A is excreted in urine and faeces, and the relative contribution of each of these routes in different species is influenced by the extent of the... 

Various in vitro assays are widely available for profiling distribution, metabolism, and pharmacokinetics (DMPK, also referred to as ADME absorption, distribution, metabolism, and excretion). Such properties of molecules are measured to ultimately predict their in vivo behavior. The metabolic stability of molecules is assessed routinely in drug discovery units by way of medium- to high-through-put assays using hepatic microsomes or hepatocytes obtained from different species (usually rat and/or human). Permeability assays (e.g., utilizing Caco-2 or MDCK cells) together with an assessment of efflux potential are also useful to troubleshoot unexpectedly low cell activity or can help select candidates for subsequent in vivo studies. 

Sex-Related Differences in Rodents. Not only are there differences in absorption, distribution, biotransformation and metabolism between species, there may also be differences between sexes within a species. Griffin et al. (1997), for example, has demonstrated sex-related differences in the metabolism of 2,4-dichlorophenoxyace-tic acid (Table 18.8). They noted that while there were differences between sexes,... 

Toxicokinetics Absorption of DCA is rapid from the intestinal tract into the bloodstream. Once in the bloodstream, DCA is distributed to the liver and muscles, and then in smaller quantities to the fat, kidney, and other tissues such as the brain and testes. The systemic clearance of DCA is significantly higher. The metabolism of DCA is mediated by a novel CST, CST-zeta found in cytosolic fraction. This enzyme appears to be subjected to autoinhibition by DCA. Although there are substantial species differences in the metabolism of DCA, autoinhibition seems to be true across the species including humans. The half-life of DCA in dogs and rats are between... 

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