Physiologically-based pharmacokinetic partition coefficients

Physiologically Based Pharmacokinetic (PBPK) Model—is comprised of a series of compartments representing organs or tissue groups with realistic weights and blood flows. These models require a variety of physiological information tissue volumes, blood flow rates to tissues, cardiac output, alveolar ventilation rates and, possibly membrane permeabilities. The models also utilize biochemical information such as air/blood partition coefficients, and metabolic parameters. PBPK models are also called biologically based tissue dosimetry models. 

Geary RS, Wall CM, Miller MA, et al. 1994. Partition coefficient measurements of diisopropyl methylphosphonate (DIMP) and trichloroethylene in rats using microdialysis and incorporated in physiologically-based pharmacokinetic (PBPK) modelling [Abstract], Society of Toxicology 33rd Annual Meeting, Dallas, TX 13-17 March, 1994. Paper No. 82. 

Another method of predicting human pharmacokinetics is physiologically based pharmacokinetics (PB-PK). The normal pharmacokinetic approach is to try to fit the plasma concentration-time curve to a mathematical function with one, two or three compartments, which are really mathematical constructs necessary for curve fitting, and do not necessarily have any physiological correlates. In PB-PK, the model consists of a series of compartments that are taken to actually represent different tissues [75-77] (Fig. 6.3). In order to build the model it is necessary to know the size and perfusion rate of each tissue, the partition coefficient of the compound between each tissue and blood, and the rate of clearance of the compound in each tissue. Although different sources of errors in the models have been... 

Poulin, P. and Theil, E.P. (2000) A priori prediction of tissue plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery. Journal of Pharmaceutical Sciences, 89, 16-35. 

Physiologically-Based Pharmacokinetics. Tissue-plasma partition coefficients may be calculated automatically by using only log P and fraction unbound in plasma as inputs. This module allows the user to simulate Cp vs. time profiles for drugs in discovery using only in silico or in vitro (metabolism) data inputs. 

Partition coefficient PolyAromatic Hydrocarbon Promoter of the alkb gene Physiologically Based PharmacoKinetic Persistent, Bioaccumulative, and toxic Path-cluster (molecular connectivity)... 

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. 

Poulin and Theil have developed a mechanistic model for estimating the Vd based on physiologically based pharmacokinetics (PBPK). For this method, the tissue plasma partition coefficient for each organ of the body is calculated by consideration of the volume fraction of neutral and phospholipids and water found in the tissues of a particular organ. For example, the volume fraction of neutral lipids in human adipose tissue is 0.79 whereas the volume fraction of neutral lipids in cardiac tissue is 0.0115. By contrast the volume fraction of water in adipose and heart are 0.18 and 0.76 respectively. Combined with the P, these volume fractions are used to estimate the distribution of a drag molecule into each tissue. Summation of the product of tissue volume and tissue/plasma partition coefficient produces the estimate of Vd. ... 

Prior to 2002, most studies published on physiologically-based pharmacokinetic models focused on the distribution and elimination of environmental toxins such as dioxin, styrene, and organic solvents [68-70]. PBPK models for drug molecules generally relied on tissue/plasma partition coefficients (Kps) measured in rat [71-73]. 

Thompson MD, Beard DA, Wu F (2012) Use of partition coefficients in flow-limited physiologically-based pharmacokinetic modeling. J Pharmacokinet Pharmacodyn 39 313-327. doi 10.1007/sl0928-012-9252-6... 

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