Absorption PBPK models

Most attempts at describing CWA PK and PD have used classical kinetic models that often fit one set of animal experimental data, at lethal doses, with extrapolation to low-dose or repeated exposure scenarios having limited confidence. This is due to the inherent nonlinearity in high-dose to low-dose extrapolations. Also, the classical approach is less adept at addressing multidose and multiroute exposure scenarios, as occurs with agents like VX, where there is pulmonary absorption of agent, as well as dermal absorption. PBPK models of chemical warfare nerve agents (CWNAs) provide an analytical approach to address many of these limitations. 

No data were located concerning whether pharmacokinetics of endosulfan in children are different from adults. There are no adequate data to determine whether endosulfan or its metabolites can cross the placenta. Studies in animals addressing these issues would provide valuable information. Although endosulfan has been detected in human milk (Lutter et al. 1998), studies in animals showed very little accumulation of endosulfan residues in breast milk (Gorbach et al. 1968 Indraningsih et al. 1993), which is consistent with the rapid elimination of endosulfan from tissues and subsequent excretion via feces and urine. There are no PBPK models for endosulfan in either adults or children. There is no information to evaluate whether absorption, distribution, metabolism, or excretion of endosulfan in children is different than in adults. 

Metabolic differences betw een humans and other animals may account for some of the interspecies differences in specific organ toxicity of trichloroethylene (see below). Among humans, sexual differences due mainly to the effects of body fat content on trichloroethylene absorption are expected based on PBPK modeling (see Section 2.3.5). 

As with classic compartment pharmacokinetic models, PBPK models can be used to simulate drug plasma concentration versus time profiles. However, PBPK models differ from classic PK models in that they include separate compartments for tissues involved in absorption, distribution, metabolism and elimination connected by physiologically based descriptions of blood flow (Figure 10.1). 

Another important advance adding to the value of PBPK modeling in the pharmaceutical industry are physiological, mechanistic models developed to describe oral absorption in humans and preclinical species. Oral absorption is a complex process determined by the interplay of physiological and biochemical processes, physicochemical properties of the compound and formulation factors. Physiologically based models to predict oral absorption in animals and humans have recently been reviewed [18, 19] and several models are now commercially available. The commercial models have not been published in detail because of proprietary reasons but in essence they are transit models segmenting the gastrointestinal tract... 

The applicability of PBPK models can be described in the context of the BDDCS classification [24]. PBPK models are very predictive for class 1 and class 2 compounds. However for poorly soluble compounds, the use of aqueous solubility is shown to be inadequate for reliable prediction of oral absorption in physiologically based models [7]. In such cases, it is recommended to use solubility measured in simulated intestinal fluids (FeSSIF, FaSSIF). Such data proved to be very relevant to simulate the oral absorption of BCS 2 (low solubility, high permeability) compounds [25]. 

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

One PBPK model for chromium has been published. The O Flaherty model (O Flaherty 1993a, 1996) simulates the absorption, distribution, metabolism, elimination, and excretion of chromium(III) and chromium(VI) compounds in the rat. Two kinetic models describing the distribution and clearance of chromium(III) compounds in humans are described at the end of this section. 

Risk assessment. The model accounts for most of the major features of chromium(VI) and chromium(III) absorption and kinetics in the rat, and reduction from the chromium(VI) to the chromium(III) valence state, but the bioavailability/absorbability of chromium from environmental sources is mostly unknown, except for bioavailability/absorbability of a few chemically defined salts. Furthermore, the mechanisms by which chromium reserves from bone tissue are released into plasma as well as age, physiological conditions and species variations are important considerations in the refinement of any PBPK model for risk assessment purposes. 

When it comes to mixtures, an important development is the use of the internal dose as a dose metric, particularly in human assessments. The internal dose is either measured directly or modeled using PBPK models, for example, as a blood or a target tissue concentration. Application of an internal dose metric makes it possible to account for 1) interindividual variability in toxicokinetics, 2) temporal variations in exposure patterns, and 3) interactions between substances during absorption, metabolism, and transport. In ecological risk assessment, internal doses are sometimes measured but rarely modeled with PBPK models. The awareness is growing that the internal dose is a useful metric but the use in formal risk assessment procedures is still limited, for separate compounds as well as for mixtures. 

Comparative Toxicokinetics. Qualitatively, absorption, distribution, metabolism, and excretion appear to be similar in humans and laboratory animals. However, quantitative variations in the absorption, distribution, metabolism, and excretion of benzene have been observed with respect to exposure routes, sex, nutritional status, and species. Further studies that focus on these differences and their implications for human health would be useful. Additionally, in vitro studies using human tissue and further research into PBPK modeling in animals would contribute significantly to the understanding of the kinetics of benzene and would aid in the development of pharmacokinetic models of exposure in humans. These topics are being addressed in ongoing studies (see Section 2.10.3). 

Route to Route PBPK models have been used for route-to-route extrapolation for specific chemicals and systems, and have been shown to produce accurate predictions in many cases [24], By assuming that the relationship between applied dose and tissue dose of the xenobiotic of interest is the same, regardless of the exposure route, route-to-route extrapolations may be performed by the addition of intake terms to the governing mass balance equations that represent each exposure pathway or mechanism. The uncertainty associated with this approach can arise from the first-pass effect as well as variations in rates and extent of absorption and metabolism from one route to another [25], However, by accounting for these route-specific processes, PBPK models can be used to conduct route-to-route extrapolations [26],... 

Overall, PBPK models can provide insight into the several aspects associated with the kinetics of a drug within the human body, collectively termed as ADMET, for absorption, distribution, metabohsm, elimination, and toxicity. An application of the PBPK models at the early stage of drug development can be useful to rapidly screen candidate drugs based on their PK properties via in silico approaches (3,4). Due to the rapid increases in the computational power, and the parallel advances in the PBPK area, the role of PBPK models in pharmacometrics is likely to substantially increase. 

The main routes of intake of a chemical are ingestion (dietary or nondietary), inhalation, dermal absorption, and parenteral (intravenous, intramuscular, intrathecal, intraperitoneal, and subcutaneous). The structure of a PBPK model is dependent on the intake routes, as the corresponding organs or tissues usually need to be explicitly modeled in order to describe the uptake of the chemical. It is therefore advisable to identify routes of uptake prior to developing the PBPK model. 

The main processes governing the pharmacokinetics of a chemical are absorption, distribution, metabolism, and excretion. In PBPK models, distribution of a chemical is characterized by blood flow rates to each organ and tissue, and partitioning of the chemical between tissue and blood. These processes are commonly modeled using two alternative types of assumptions flow-Umited and diffusion-limited transport. The flow-limited assumption implies that equilibration between free and bound fractions in blood and tissue is rapid, and that concentrations of the chemical in the venous blood exiting a tissue and in the tissue are at equilibrium. The tissue is assumed to be a homogeneous... 

The chloroform PBPK model describes intake from inhalation, dermal absorption from either water or air, and oral ingestion from drinking water. The intravenous injection route is also added in this model so that it can be used for other chemicals. The corresponding media concentrations of chloroform, in the air, drinking water, and shower water, are dependent on the exposure scenario and hence are to be provided as model inputs. 

PBPK models for 2-butoxyethanol are discussed below. No specific models were found for 2-butoxy-ethanol acetate. However, it is expected that 2-butoxyethanol acetate follows a similar model after absorption and conversion to 2-butoxyethanol. However, the absorption of 2-butoxyacetic acid may be different from 2-butoxyethanol because of its different chemical form. 

PBPK models of 2-butoxyethanol absorption, metabolism, disposition, and excretion have been published by Johanson and coworkers (Johanson 1986, 1991a Johanson and Naslund 1988), Shyr et al. (1993), and Corley et al. (1994). They are presented in the order that they were published in the literature, since each... 

The absorption, distribution, metabolism, and excretion of 2-butoxyethanol are relatively well understood, leading to a number of PBPK models (Corley 1996 Corley et al. 1994 Johanson 1986, 1991a Johanson and Naslund 1988 Shyr et al. 1993). Tliese models have been validated with acute- and intermediate-duration pharmacokinetic data. Chronic pharmacokinetic data would be useful so that the models could be validated for chronic exposure. Additional studies designed to define the differences and similarities between 2-butoxyethanol and its acetate with regard to absorption, distribution, metabolism, and excretion would be useful to establish these parameters for to 2-butoxyethanol acetate. 

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