Human organs, computer models

The distribution of a compound in the human body can also be partially related to the absorption properties. There are specific transport systems that are expressed in certain tissues that can influence the distribution of the compound. For example, rosuvastatin, a new member of the statin family is transported by the OATP-C carrier system, which is selectively expressed in the liver, making this compound selectively distributed into this organ [27]. In general it is not possible to derive computational models for these selective transport systems since there is not yet enough experimental information and data to support the model building and validation. Nevertheless, there are three properties that are commonly used to describe the distribution of a compound in the human body the solubility, the unspecific binding of the compound to plasma proteins and the volume of distribution. 

Organic chemists and chemists in related fields use computers to analyze the structure and motion of molecules. Sometimes they build a visual model of one molecule. Other times they examine entire molecular systems. This information is essential in finding new drugs and in mapping human genes. Molecular modeling is one of the fastest-growing fields in science. 

More sophisticated in vitro systems exist, such as human on chip microsystems, in which various cell types are cultivated in different miniaturized chambers linked by a microfluidic network in which a cell culture medium is circulated to mimic blood flow through organs [5, 6]. However, even in that case, we need extrapolation modelling to scale up the data obtained to the target animal species (typically humans). A purely experimental approach would also be quite expensive if PK were to be predicted for various dosing schedules and levels. We will see in the following section how PBPK computational models can help. 

Fig. 2.7 The ozone hole over Antarctica in September of 2005 covered an area of more than 24 million square kUometers which is approximately equal to the area of North America. The ozone hole has been forming in the stratosphere over Antarctica since about 1970 as a result of the release of anthropogenic CFC gases into the atmosphere. Computer models now predict that the size of the ozone hole will begin to decline in 2018 and will stop forming altogether in 2068. This is good news because the ozone of the stratosphere absorbs ultraviolet radiation which can cause skin cancer and eye damage in humans and is harmM to marine organisms. The ozone content of the stratosphere over Antarctica has declined annually by about 70% below normal during September and October whereas the decline over the USA has only been between 3% and 6% (Cook-Andersen 2006 Photo courtesy of NASA)...

Diao L, Ekins S, Polli JE (2009) Novel inhibitors of human organic cation/carnitine transporter (hOCTN2) via computational modeling and in vitro testing. Pharm Res 26 1890-1900. 

In general, organ doses carmot be measured directly they have to be calculated by radiation transport simulations, mostly using Monte Carlo techniques and computational models of the human body. The results of these calculations are so-called organ dose conversion coefficients, i.e., mean organ doses normalized to a measurable dose quantity, such as the CTDl (see below). 

Much of the interest in using predictive modeling of human Pb exposures concerns mechanistic, i.e., biokinetic, models. Biokinetic models differ from site-specific or multisite ad hoc/slope factor models in a number of important ways. Eirst, they are constructed (by definition) within a computational and biological/kinetic framework. That framework specifies inclusion of all identified parameters representing mechanisms by which environmental Pb is deposited in and removed from human organs and tissues. Mechanistic models are structured to be much more complex than the regression models... 

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