Physiologically based pharmacokinetic activity

Once a chemical is in systemic circulation, the next concern is how rapidly it is cleared from the body. Under the assumption of steady-state exposure, the clearance rate drives the steady-state concentration in the blood and other tissues, which in turn will help determine what types of specific molecular activity can be expected. Chemicals are processed through the liver, where a variety of biotransformation reactions occur, for instance, making the chemical more water soluble or tagging it for active transport. The chemical can then be actively or passively partitioned for excretion based largely on the physicochemical properties of the parent compound and the resulting metabolites. Whole animal pharmacokinetic studies can be carried out to determine partitioning, metabolic fate, and routes and extent of excretion, but these studies are extremely laborious and expensive, and are often difficult to extrapolate to humans. To complement these studies, and in some cases to replace them, physiologically based pharmacokinetic (PBPK) models can be constructed [32, 33]. These are typically compartment-based models that are parameterized for particular... 

A physiologically based pharmacokinetic model for predicting ethylene dibromide kinetics and consequent toxicity, based on in-vitro metabolic parameters of rodents and humans and on the use of scaling factors, has been presented (Ploemen et al., 1997). Its most important prediction is that the GST pathway is significantly active even at low ethylene dibromide concentrations, which has important implications for risk assessment. 

Tan, C., K. Liao, and H.J. Clewell. 2005. Physiologically based pharmacokinetic modeling as a tool to interpret human biomonitoring data. CUT Activities 25(4) l-6. 

Many types of modeling techniques are available in the discovery phase of drug development, from structure activity relationships (SAR) to physiology based pharmacokinetics (PBPK) and pharmacokinetics-/pharmacodynamics (PK/PD) to help choosing some of the lead compounds. Some tests that are carried out by discovery include techniques related to structure determination, metabolism, and permeability NMR, MS/MS, elemental analysis, PAMPA, CACO-2, and in vitro metabolic stability. Although they are important as a part of physicochemical molecular characterization under the biopharmaceutics umbrella, they will not be discussed here. The reader can find relevant information in numerous monographs [9,10]. 

Little information is available on the acute toxicity of hexachlorobutadiene in humans. Recent physiologically based pharmacokinetic models suggest an order of magnitude lower activation of reactive nephrotoxic metabolics in humans compared to rats. 

Hazard identification is the step in the risk assessment that qualitatively characterizes the inherent toxicity of a chemical. Scientific data are evaluated to establish a possible causal relationship between the occurrence of adverse health effects and chemical exposure. This step includes characterization of acute, subchronic, and chronic effects the potential for local versus systemic effects the influence of the route of exposure the relevance, to humans, of effects seen in animals an evaluation of the biological importance of the observed effects the likelihood of the effects occurring under certain conditions and the potential implications for public health. This step should be based on a thorough review of all the data that may provide information that is relevant to evaluating the potential chemical hazard. This may include data describing the effects on a variety of test animals, in vitro studies that characterize mechanisms of toxicity, metabolism, physiologically based pharmacokinetic studies, structure-activity relationships, short-term human studies, and epidemiological studies. Animal studies may focus on particular types of effects and may include reproductive toxicity studies,... 

This chapter reviews some of the in silico attempts to predict oral bioavailability. However, bioavailability is a complex property, and various pros and cons of current quantitative structure-activity relationship (QSAR) based approaches will be discussed here. As an alternative, physiologically-based pharmacokinetic (PBPK) modeling is discussed as a promising approach to predict and simulate pharmacokinetics (PK), including estimating bioavailability. 

Proposed Pathway for Formation of Dimethyl Selenide from Selenite in Animals 3-6. Activation and Reduction of Selenate to Selenite in Yeast Saccharomyces cerevisiae 3-7. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance 3-8. Selenite Model, a Kinetic Model for Selenite Metabolism 3-9. Selenomethionine Model, a Kinetic Model for Selenomethionine Metabolism 3-10.Existing Information on Health Effects of Selenium 6-1. Frequency of NPL Sites with Selenium Contamination... 

Xu L, Eiseman J L, Egorin M J, et al. (2003). Physiologically-based pharmacokinetics and molecular pharmacodynamics of 17- (allylamino)-17-demethoxygeldanamycin and its active metabolite in tumor-bearing mice. J. Pharmacokinet. Pharmacodyn. 30 185-219. 

While ejqierimental methods always require sufficient amount of chemicals for the estimation of drag absorption, computational in silico) methods can lead to the prediction of intestinal absorption based on chemical structure, and can thus be used before synthesis of compoimds. In silico predictions could be based both on relatively simple quantitative structure-activity relationships (QSAR) analysis and more complex physiologically based pharmacokinetic and/or pharmacodynamic models. Whichever the approach used for model building, computational methods should be based on experimental data that were obtained for a wide range of structurally diverse compoimds (training set). It should be noted, however, that current in silico methods, are not as reliable as experimental models. 

Potts RO, Guy RH (1992) Predicting skin permeability. Pharm Res 9 663-669 Potts RO, Guy RH (1995) A predictive algorithm for skin permeability the effects of molecular size and hydrogen bond activity. Pharm Res 12 1628-1633 Poulin P, Theil F-P (2000) A priori prediction of tissue plasma partition coefficients of thugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery. J Pharm Sci 89 16-35... 

Due to its central role in toxicant metabolism, the liver is one of the first organs being constructed in the Virtual Tissue Research Project. Physiologically based pharmacokinetic modeling, cellular systems, and molecular networks are integrated to mimic the multitude of activities performed by the liver. Once completed, this innovative project will be an invaluable resource for accessible, accurate, and responsible prediction of liver toxicity. 

As an oral, triple pro-drug, capecitabine has been designed to deliver specifically 5-FU in tumor cells, and as such its pharmacokinetics profile should not be strongly affected by erratic DPD activity in the liver (36). Nevertheless, because the enzymes supporting final activation of capecitabine can be expressed in hepatocytes too, early synthesis of 5-FU may occur in the liver, thus leading eventually to plasma overexposure, as confirmed by a physiologically-based PK model (37). 

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