Elimination PBPK models

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. 

Monte Carlo simulation, an iterative technique which derives a range of risk estimates, was incorporated into a trichloroethylene risk assessment using the PBPK model developed by Fisher and Allen (1993). The results of this study (Cronin et al. 1995), which used the kinetics of TCA production and trichloroethylene elimination as the dose metrics relevant to carcinogenic risk, indicated that concentrations of 0.09-1.0 pg/L (men) and 0.29-5.3 pg/L (women) in drinking water correspond to a cancer risk in humans of 1 in 1 million. For inhalation exposure, a similar risk was obtained from intermittent exposure to 0.07-13.3 ppb (men) and 0.16-6.3 ppb (women), or continuous exposure to 0.01-2.6 ppb (men) and 0.03-6.3 ppb (women) (Cronin et al. 1995). 

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). 

Some caution is required with some chemical classes and compound properties related to low solubility, high lipophihcity, major impact of active transport processes on elimination and distribution. It is therefore recommended that PBPK models should only be applied after verification of the simulations with in vivo pharmacokinetics for a few compounds of a given chemical class. Such verification will help to identify invalid model assumptions or missing processes where additional data is needed. 

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. 

There were no PBPK models for aluminum located in the literature. However, physiologically and mechanistically based models have been developed using basic information for estimating the deposition and elimination of a range of compounds one recent model is described in ICRP (1994). Although this model is not specific to aluminum, it provides information that may be useful for risk assessment, tissue dosimetry, and species extrapolations. 

The elimination of 2,3,7,8-TCDD from humans was evaluated using a PBPK model developed by Kissel and Robarge (1988). The steady-state adipose tissue concentration predicted by the model was similar to the lipid-based blood levels reported in the general population with no known special exposure to... 

In the mechanistic models used to predict toxic effects of time-variable exposure to organisms, a distinction can be made between 1-step models and 2-step models (Ashauer et al. 2006). One-step models only consider toxicokinetics, whereas 2-step models consider both toxicokinetics and toxicodynamics. One-step models try to describe the uptake and elimination of a given compound in an organism and relate the calculated internal concentration to the effect occurring. Usually, an average total body residue is calculated, assuming that the concentration at the actual site(s) of action will be linearly related to the total body concentration. In specific cases, it may be necessary to calculate the concentration at the site of action through the use of more refined multicompartment (PBPK) models. 

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. 

PBPK models require three different types of information (1) partition coefficients that describe the relative solubility or affinity of the compound for blood versus other tissues (2) physiological constants, such as tissue and organ volumes and the relevant blood flows and (3) rate constants for the key elimination pathways. 

Often, PBPK models for toxicokinetics application require special considerations (e.g., volatile toxicants may incur tissue-air partition coefficients and alveolar elimination rates). Partition coefficients are generally obtained by measurement in the laboratory, tissue volume/blood flow data are mostly available from the scientific literature (with allometric scaling from species to species), and biotransformation data are usually obtained from in vivo and in vitro kinetic studies. Biochemical constants for metabolic pathways are captured using the maximum rate of reaction, or Vmax5 and the binding affinity of the particular substrate for the metabolizing enzyme. 

PBPK models are particularly useful for interspecies extrapolations of dose-response data. In using a PBPK model of uptake, distribution, and elimination, an exponential power (e.g., 0.75) of the body weight is used to scale the cardiac output and ventilation rate between the laboratory species (typically rat) and humans. A PBPK model will therefore contain adequate logic to account for routes of administration, storage tissues and residence time therein, elimination rates, and sufficient mathematical detail to mimic the integration of these processes. It is important that the model parameters (e.g., elimination rates) be validated as much as possible by separate kinetic studies in the relevant species. The ultimate test of the model is how the model predictions are for parameters such as blood levels, rate of metabolism, and tissue concentrations relative to real-life animal data for the chemical. 

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. 

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]. 

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. 

There appears to be large differences in the manner and rate of absorption of the pyrethroids from the gastrointestinal tract, implying that GI advanced compartmen-tal transit models (ACAT) need to be included in PBPK models. This is especially true of the absorption of an oral dose of tefluthrin in male rats, in which 3.0-6.9%, 41.3-46.3%, and 5.2-15.5% of the dose is eliminated in urine, feces, and bile, respectively (0-48 h after administration). Several percutaneous studies with the pyrethroids strongly support the belief that these insecticides are not readily absorbed, but remain on the surface of the skin until they are washed off. In one particular study (Sidon et al. 1988) the high levels of permethrin absorption through the forehead skin (24—28%) of the monkey was reported over a 7- to 14-days period. Wester et al. (1994) reported an absorption of 1.9% of pyrethrin that had been applied to the forearm of human volunteers over a 7-days period. 

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