Metabolism model comparisons

Eisele GR, Bernard SR, Nestor CW. 1987. Gastrointestinal absorption of americium-241 by orally exposed swine Comparison of experimental results with predictions of metabolic models. Radiat Res 112 62-73. 

Mewhinney JA, Griffith WC, Muggenburg BA. 1979. Comparison of metabolic models used to describe the fate of inhaled 241Am02 based on inhalation studies in the beagle dog. Health Phys 37(6) 830. 

W. H. Barr and S. Riegelman, Intestinal drug absorp- 28. tion and metabolism. I. Comparison of methods and models to study physiological factors in vitro and in... 

Portner R, Schafer T (1996), Modeling hybridoma cells growth and metabolism - a comparison of selected models and data, J. Biotechnol. 49 119-135. 

Tirona, R., Schwab, A., Geng, W., and Pang, K., Hepatic clearance models Comparison of the dispersion and Goresky models in outflow profiles from multiple indicator dilution rat liver studies, Drug Metabolism and Disposition, Vol. 26, No. 5, 1998, pp. 465-475. 

Comparison of Laboratory Rodents and Sub-human Primates as Metabolic Models for Man... 

Zuegge J, Schneider G, Coassolo P, Lave T. Prediction of hepatic metabolic clearance comparison and assessment of prediction models. Clin Pharmacokinet 2001 40 553-563. 

Elinder CG, Piscator M, Linnman L (1977) Cadmium and zinc relationships in kidney cortex, liver and pancreas. Environ. Res. 13 432-440 Elinder CG, Kjellstrom T, Linnman L, Pershagen G (1978a) Urinary excretion of cadmium and zinc among persons from Sweden. Environ. Res. 15 473-484 Elinder CG, Kjellstrom T, Lind B, Molander M-L, Silander T (1978b) Cadmium concentrations in human liver, blood, and bile Comparison withi a metabolic model. Environ. Res. 17 236-241... 

One can, however, attempt to sidestep some of the above constraints to acquiring measurement data in epidemiological smdies through exposure simulations, if Pb input measurements are available. This would be the case with biokinetic or metabolic models. This would also be the case in some situations where ad hoc or statistical empirical models derived from a modeled relationship for a particular site and set of environmental Pb site parameters were applied to other sites very similarly simated. The relative flexibility of the ad hoc or setting-specific empirical models may or may not be less widely applicable, i.e., more problematic, than various metabolic models. The relative merits of these model forms emerge through comparisons contrasting measured to simulated or predicted data outputs. 

Portner, R. and Schafer, T. (1996) Modelling hybridoraa cell growth and metabolism—a comparison of selected models and data. / Biotechnol, 19 (1-3), 119-135. 

Freiding, S., Gutsche, K.A., Ehrmann, M.A., and Vogel, R.F. (2011) Genetic screening of Lactobacillus sakei and Lactobacillus curvatus strains for their peptidolytic system and amino acid metabolism, and comparison of their volatilomes in a model system. SystAppl Microbiol 34, 311-320. 

Comparative Toxicokinetics. In humans, the targets for trichloroethylene toxicity are the liver, kidney, cardiovascular system, and nervous system. Experimental animal studies support this conclusion, although the susceptibilities of some targets, such as the liver, appear to differ between rats and mice. The fact that these two species could exhibit such different effects allows us to question which species is an appropriate model for humans. A similar situation occurred in the cancer studies, where results in rats and mice had different outcomes. The critical issue appears to be differences in metabolism of trichloroethylene across species (Andersen et al. 1980 Buben and O Flaherty 1985 Filser and Bolt 1979 Prout et al. 1985 Stott et al. 1982). Further studies relating the metabolism of humans to those of rats and mice are needed to confirm the basis for differences in species and sex susceptibility to trichloroethylene s toxic effects and in estimating human heath effects from animal data. Development and validation of PBPK models is one approach to interspecies comparisons of data. 

Droloxifene (3-hydroxy-tamoxifen) behaves as an estrogen agonist in bone tissue and several lipid and coagulation markers in castrated rat models and does not show stimulation of the endometrial epithelium in preclinical studies (Ke et al. 1997). Endometrial stimulation has, however, been observed in clinical trials, which, together with the fact that as an estrogen agonist it is ten times less potent than tamoxifen in bone tissue and lipid metabolism (Hendrix et al. 2001) and that in a recent head-to-head comparison with tamoxifen droloxifene was demonstrated not to be superior in any parameter of breast cancer treatment efficacy (Buzdar et al. 2002), has resulted in cancellation of its clinical development. 

Recent work in our laboratories has confirmed the existence of a similar pathway in the oxidation of vindoline in mammals (777). The availability of compounds such as 59 as analytical standards, along with published mass spectral and NMR spectral properties of this compound, served to facilitate identification of metabolites formed in mammalian liver microsome incubations. Two compounds are produced during incubations with mouse liver microsome preparations 17-deacetylvindoline, and the dihydrovindoline ether dimer 59. Both compounds were isolated and completely characterized by spectral comparison to authentic standards. This work emphasizes the prospective value of microbial and enzymatic transformation studies in predicting pathways of metabolism in mammalian systems. This work would also suggest the involvement of cytochrome P-450 enzyme system(s) in the oxidation process. Whether the first steps involve direct introduction of molecular oxygen at position 3 of vindoline or an initial abstraction of electrons, as in Scheme 15, remains unknown. The establishment of a metabolic pathway in mammals, identical to those found in Strep-tomycetes, with copper oxidases and peroxidases again confirms the prospective value of the microbial models of mammalian metabolism concept. 

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. 

Experimental aquatic metabolism systems have taken one of four forms -- static water in ordinary aquaria, jars, or beakers static "model ecosystems" static outdoor ponds and continuously-flowing systems (Table 1). A very rough comparison of their advantages is shown in Table II. For example, while the static aquaria doubtless are by far the... 

Sinko et al. [92] established an Intestinal and Vascular Access Port (IVAP) model where dogs were fitted with three intestinal catheters for site-specific administration to various section of the intestine (i.e. duodenum, ileum, and colon), one vascular catheter for access to the portal vein, and a peripheral vein (e.g. branchial) for IV access. The animals were allowed to recover for 2 weeks prior to initiation of studies. The extent of intestinal versus hepatic first-pass metabolism was determined by comparing blood levels following intra-duodenal (AUQ.d.) versus portal (AUVi.p.v.) versus intravenous (AUQ.V.) administration. The model also lends itself to a comparison of the impact of site-specific preferential absorption, and hence a determination of the optimal site for intestinal delivery. 

Early IPL studies focused mostly on the metabolism of the bronchodilators and corticosteroids or the pharmacological activity of bronchodilators on the ex vivo preparation. Recently, the absorptive transfer of beclomethasone dipro-prionate (BDP) has been measured following administration to the human lung reperfusion model by two different commercially available inhalers for which human pharmacokinetic data are available for comparison [43],... 

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