Physiologically-based pharmacokinetic developing models

FUN tool is a new integrated software based on a multimedia model, physiologically based pharmacokinetic (PBPK) models and associated databases. The tool is a dynamic integrated model and is capable of assessing the human exposure to chemical substances via multiple exposure pathways and the potential health risks (Fig. 9) [70]. 2-FUN tool has been developed in the framework of the European project called 2-FUN (Full-chain and UNcertainty Approaches for Assessing Health Risks in FUture ENvironmental Scenarios www.2-fun.org). 

Physiologically Based Toxicokinetic (PBTK) models are derived similarly to Physiologically Based Pharmacokinetic (PBPK) models, which have been used for a number of years in the development of medicinal drugs. They describe the rat or man as a set of tissue compartments, i.e., liver, adipose tissues, poorly perfused tissues, and richly perfused tissues along with a description of metabolism in the liver. In case of volatile organic compounds a description of gas exchange at the level of the lung is included, see also Section 4.3.6. 

Physiologically-based pharmacokinetic (PBPK) models have been developed for a number of drugs and chemicals, in order to better understand and simulate the dynamics of those compounds in the body. Advances made to date indicate that valid PBPK models can accurately predict the... 

Poulin and Krishnan (1995) developed a method to predict tissue blood PCs for incorporation into physiologically based pharmacokinetic (PBPK) models. Tissue blood partitioning was calculated as an additive function of partitioning into the water, neutral lipids and phospholipids constituent of individual tissues. These were calculated using published values for lipid and water content of tissues and the octanol-water PC of the compounds. Poulin and Krishnan (1998 1999) used this method to predict tissue blood PCs that were subsequently incorporated into a quantitative structure-toxicokinetic model. The prediction of tissue plasma PCs to describe distribution processes and as input parameters for PBPK models has been extensively researched by Poulin and coworkers a great deal of further information can be obtained from their references (Poulin and Theil, 2000 Poulin et al., 2001 Poulin and Theil, 2002a Poulin and Theil, 2002b). 

A physiologically based pharmacokinetics (PBPK) model based on the ventilation rate, cardiac output, tissue blood flow rates, and volumes as well as measured tissue/air and blood/air partition coefficients has been developed (Medinsky et al. 1989a Travis et al. 1990). Experimentally determined data and model simulations indicated that during and after 6 hours of inhalation exposure to benzene, mice metabolized benzene more efficiently than rats (Medinsky et al. 1989a). After oral exposure, mice and rats appeared to metabolize benzene similarly up to oral doses of 50 mg/kg, above which rats metabolized more benzene than did mice on a per kg body weight basis (Medinsky et al. 1989b). This model may be able to predict the human response based on animal data. Benzene metabolism followed Michaelis-Menton kinetics in vivo primarily in the liver, and to a lesser extent in the bone marrow. Additional information on PBPK modeling is presented in Section 2.3.5. 

No physiologically based pharmacokinetic (PBPK) models are available for tetrahydrofuran in animals. Based on human volunteer studies, a PBPK model for tetrahydrofuran was developed which predicts rapid elimination of tetrahydrofuran from the body. The human PBPK model predicts that repeated inhalation exposure of 200 ppm would yield end of the work shift levels of tetrahydrofuran of 5.1 ppm in breath, 57moll in the blood, and 100mol in the urine. 

Simulation methods have also been developed that include physiologically based pharmacokinetic modeling (PBPK) and methods such as Cloe PK, OMPPPlus, GastroPlus , SimCYP , and others [122] that are described elsewhere in this book. It is likely that the computational metabolism predictions could be integrated with these to assist in deriving more accurate predictions of human pharmacokinetic parameters. 

Clewell HJ 3rd, Gentry PR, Covington TR, Gearhart JM. Development of a physiologically based pharmacokinetic model of trichloroethylene and its metabolites for use in risk assessment. Environ Health Perspect 2000 May 108 Suppl 2 283-305. 

Charnick SB, Kawai R, Nedelman JR, Lemaire M, Niederberger W, Sato H. Perspectives in pharmacokinetics. Physiologically based pharmacokinetic modeling as atoolfor drug development./P/jarmacokmefTEop/jarm 1995 Apr 23(2) 217-29. Review. 

Theil FP, Guentert TW, Haddad S, Poulin P. Utility of physiologically based pharmacokinetic models to drug development and rational drug discovery candidate selection. Toxicol Lett 2003 Feb 18 138(l-2) 29-49. Review. 

The Chemical Manager and Authors acknowledge the contribution of Dr. Ted W. Simon, U.S. EPA, in applying physiologically-based pharmacokinetic modeling to the development of minimal risk levels for trichloroethylene. 

Physiologically based pharmacokinetic models provide a format to analyze relationships between model parameters and physicochemical properties for a series of drug analogues. Quantitative structure-pharmacokinetic relationships based on PB-PK model parameters have been pursued [12,13] and may ultimately prove useful in the drug development process. In this venue, such relationships, through predictions of tissue distribution, could expedite drug design and discovery. 

Absorbed lead is distributed in various tissue compartments. Several models of lead pharmacokinetics have been proposed to characterize such parameters as intercompartmental lead exchange rates, retention of lead in various pools, and relative rates of distribution among the tissue groups. See Section 2.3.5 for a discussion of the classical compartmental models and physiologically based pharmacokinetic models (PBPK) developed for lead risk assessments. 

Other major early contributions of biochemical engineering have been in the development of the artificial kidney and physiologically based pharmacokinetic models. The artificial kidney has been literally a lifesaver. Pharmacokinetic models divide the body of an animal or human into various compartments that act as bioreactors. These mathematical models have been used very successfully in developing therapeutic strategies for the optimal delivery of chemotherapeutic drugs and in assessing risk from exposure to toxins. 

Andersen ME (1995) Development of physiologically based pharmacokinetic and physiologically based pharmacodynamic models for applications in toxicology and risk assessment. Toxicol Lett 79 35-44... 

Mirfazaelian A, Kim K, Anand SS, Kim HJ, Tomero-Velez R, Bruckner JV, Fisher JW (2006) Development of a physiologically based pharmacokinetic model for deltamethrin in the adult male Sprague-Dawley rat. Toxicol Sci 93(2) 432-442... 

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