Model physiological

In most experiments, it is not possible to measure the concentrations in the vascular, interstitial, and intracellular spaces separately. Usually, the total concentration within an organ, c,- is measured  

Obviously, a physiological model can be quite complex and is not easily applied in its full detail. Simplifications are helpful some of the most common and useful simphfications are provided in the next subsections. 

Organs that are not well perfused are termed flow limited. In these cases, the intracompartmental fluxes, and are much greater than the flow 

If the organ is reasonably well perfused (i.e., the flow-limited conditions are not satisfied), the full physiological pharmacokinetic treatment may be reduced by assuming the organ is membrane limited. Here, the limitation on transport is assumed to occur at either the capillary membrane separating the vascular and interstitial compartments or the plasma membranes separating the interstitial and intracellular compartments. For example, when the net flux between the interstitial and intracellular compartments is much slower than the net flux between the vascular and interstitial compartments and the plasma flow rate, the three-compartment model can be reduced to a two-compartment model  

Drug Elimination. Excretion or metabolism can be added to an appropriate compartment, as indicated by the terms eiim in Equation 7-18. A full description of enzyme-mediated metabolic pathways usually employs Michaelis-Menten kinetics  

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FIGURE 5.41 <<]) Physiological model for phenobarbital. (b) Physiological model for the voJaule... 

Clewell HI 111, Andersen ME. 1985. Risk assessment extrapolations and physiological modeling. Toxicol Ind Health 1 111-113. 

Droz PO, Wu MM, Cumberland WG. 1989a. Variability in biological monitoring of organic solvent exposure. II. Application of a population physiological model. BrJ Ind Med 46 547-558. 

Fisher JW. 1993. Estimating the risks of liver and lung cancer in humans exposed to trichloroethylene using a physiological model. Toxicol Lett 68 127-129. 

Fisher JW, Allen BC. 1993. Evaluating the risk of liver cancer in humans exposed to trichloroethylene using physiological models. Risk Anal 13 87-95. 

Farris FF, Dedrick RL, Allen PV, Smith JC. 1993. Physiological model for the pharmacokinetics of methyl mercury in the growing rat. Toxicol Appl Pharmacol 119 74-90. 

F. F. Farris, R.L. Dedrick, P.V. Allen and J.C. Smith, Physiological model for the pharmacokinetics of methyl mercury in the growing rat. Toxicol. Appl. Pharmacol., 119 (1993) 74—90. P. Franklin, An Introduction to Fourier Methods and the Laplace Transformation. Dover, New York, 1958. 

FG King, RL Dedrick. Physiological model for the pharmacokinetics of 2 -deoxyco-formycin in normal and leukemic mice. J Pharmacokin Biopharm 9 519-534, 1981. 

Physiological modeling Scientific literature Scientific speculation Indication... 

Bungay PM, Dedrick RL, Matthews HB. 1982. Physiological modeling of enteric transport. Air Force Aerospace Medical Research Laboratory, Proceedings of the 12th Conference on Environmental Toxicology, 1981, 287-298. 

WillmanS, Schmitt W, Keldenich J, Dressman JB (2003) A physiologic model for simulating gastrointestinal flow and drug absorption in rats. Pharm. Res. 20 1766— 1771. 

Willman S, Schmitt W, Keldenich J, Lippert J, Dressman JB (2004) A Physiological model for the estimation of the fraction dose absorbed in humans. J. Med. Chem. 47 4022-4031. 

Bois FY, Smith MT, Spear RC. 1991. Mechanisms of benzene carcinogenesis Application of a physiological model of benzene pharmacokinetics and metabolism. Toxicol Lett 56 283-298. 

First, the procedure now used by the EPA for inhalation data differs from what we have described above, in that the ten-fold factor for interspecies extrapolation (animal-to-human) is dropped in favor of a specific model that describes the well-known physiological differences between animals and humans that affect the relative rates of movement of a given administered dose of a chemical in the respiratory tracts of animals and humans. These physiological models provide fairly accurate predictions of the relative doses of chemicals delivered into the respiratory regions of animals and humans who have received identical administered (inhaled) doses. The estimate of delivered dose offers a well-accepted scientific approach to at least part of the problem of interspecies differences. Details of the delivered dose calculations are beyond the scope of this book (see references in Sources and recommended reading). 

Physiological model used to describe the pharmacokinetics of chloroform In rats, mice, and humans during inhalation, oral, and intraperitoneal exposures. 

Similar equations have been derived by other authors, using various types of compart-mental models [40,48] (Section 13.2.4.1) or simplified physiological models [44,45,48] (Section 13.2.4.2), demonstrating that the choice of the model is not critical in the derivation of... 

There are several approaches to pharmacokinetic modelling. These include empirical, compartmental, clearance-based and physiological models. In the latter full physiological models of blood flow to and from all major organs and tissues in the body are considered. Such models can be used to study concentration-time profiles in the individual organs and e. g. in the plasma [57-60]. Further progress in this area may result in better PK predictions in humans [61]... 

Haddad, S., G. Charest-Tardif, R. Tardif, and K. Krishnan. 1999b. Physiological modelling of the toxicokinetic interactions in a quarternary mixture of aromatic hydrocarbons. Toxicol. Appl. Pharmacol. 161 249-257. Haddad, S., G. Charest-Tardif, R. Tardif, and K. Krishnan. 2000a. Validation of a physiological modelling framework for simulating the toxicokinetics of chemicals in mixtures. Toxicol. Appl. Pharmacol. 167 199-209. 

This is the realm of in silica simulations, text mining, database management, classic in silica qualitative SAR modeling and physiology modeling. 

Parrott, N., Jones, H., Paquereau, N. and Lave, T. (2005) Application of fidl physiological models for pharmaceutical drug candidate selection and extrapolation of pharmacokinetics to man. Basic Clinical Pharmacology and Toxicology, 96, 193—199. 

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