Oral route pharmacokinetic modeling

Interroute Extrapolation. The Corley model used three routes of administration, intraperitoneal, oral and inhalation, in rats and mice to describe the disposition of chloroform. This data was validated for humans by comparing the model output using the animal data with actual human data from human oral chloroform pharmacokinetic studies. Using the human pharmacokinetic constants from the in vitro studies conducted by Corley, the model made adequate predictions of the amount of chloroform metabolized and exhaled in both males and females. 

Absorption, Distribution, Metabolism, and Excretion. Levels of cresols in blood were obtained from a single case report of a dermally exposed human (Green 1975). Data on the toxicokinetics of cresols in animals were contained in two acute oral studies that provided only limited quantitative information on the absorption, metabolism, and excretion of cresols (Bray et al. 1950 Williams 1938). A more complete oral toxicokinetics study, in addition to studies using dermal and inhalation exposure, would provide data that could be used to develop predictive pharmacokinetic models for cresols. Inclusion of several dose levels and exposure durations in these studies would provide a more complete picture of the toxicokinetics of cresols and allow a more accurate route by route comparison, because it would allow detection of saturation effects. Studies of the tissue distribution of cresols in the body might help identify possible target organs. 

Interroute Extrapolation. The model is designed to simulate the pharmacokinetics of DEHP and its metabolite, MEHP, when exposure is by the oral route. The pharmacokinetics of DEHP would be expected to be different for other routes of exposure therefore, the output of the model cannot be extrapolated to other routes (e.g., dermal, inhalation) without modification of the model. Calibration and validation studies utilized gavage exposures for oral dosing, and therefore, the model might not be applicable to other oral exposure pathways (e.g., dietary, drinking water) without modification. 

The key pharmacokinetic parameters to be considered in drug development are discussed here, vide infra. Although this is not an exhaustive list, successful modeling of these key parameters would provide a useful preliminary screening tool. The properties are presented in the order in which a xenobiotic entering the body via the oral route would be exposed to them, rather than in order of priority. 

Let us now explore the applications of these methods to calculate the MRT for another important pharmacokinetic model, namely the one-compartment model with extravascular route of administration. In the following discussion, though the oral route is specified in the derivations, the results apply to any other extravascular route of drug administration. For a one-compartment drug administered orally, the equation for mass of drug in the body (excluding the gastrointestinal tract, which is treated by... 

Validation of the Model. The Corley model was validated using chloroform data sets from oral (Brown et al. 1974a) and intraperitoneal (Ilett et al. 1973) routes of administration and from human pharmacokinetic studies (Fry et al. 1972). Metabolic rate constants obtained from the gas-uptake experiments were validated by modeling the disposition of radiolabeled chloroform in mice and rats following inhalation of chloroform at much lower doses. For the oral data set, the model accurately predicted the total amounts of chloroform metabolized for both rats and mice. 

Many laboratory animal models have been used to describe the toxicity and pharmacology of chloroform. By far, the most commonly used laboratory animal species are the rat and mouse models. Generally, the pharmacokinetic and toxicokinetic data gathered from rats and mice compare favorably with the limited information available from human studies. PBPK models have been developed using pharmacokinetic and toxicokinetic data for use in risk assessment work for the human. The models are discussed in depth in Section 2.3.5. As mentioned previously, male mice have a sex-related tendency to develop severe renal disease when exposed to chloroform, particularly by the inhalation and oral exposure routes. This effect appears to be species-related as well, since experiments in rabbits and guinea pigs found no sex-related differences in renal toxicity. 

In addition, no studies were located regarding absorption, distribution, metabolism, or excretion in animals after inhalation or dermal exposure to 2,4-DNP. Therefore, pharmacokinetic studies in animals exposed to 2,4-DNP by the inhalation, oral, and dermal routes would be useful in determining differences among these routes and may help to identify a suitable model to assess potential differences in pharmacokinetics via these routes in humans. 

Model refinement and validation for both the chltnpyrifos and the diazinon PBPK/PD models wa.s accomplished by conducting a scries of in vivo pharmacokinetic and pharmacodynamic studies in the rat and by evaluating the capability of the model to accurately simulate in vivo data published in the literature. The experimental details are fully described in Timchalk et ai (2002b) and Poet et at. (2004). In brief, these studies involved an acute oral exposure to chlorpyrifos or diazinon and the blood time course of the parent compounds and metabolites was determined, as well as the time course for the cholinesterase inhibition in several tissues. Representative results and model simulations are presented in Fig. 12 and 13 for the pharmacokinetic and pharmacodynamic response in rats following comparable oral doses (50 and 100 mg/kg) of chlorpyrifos and diazinon, respectively, The overall response was fairly comparable for these two insecticides, and the models reasonably simulated both dosimetry and the dose-dependent cholinesterase inhibition. These results arc very consistent with a fairly rapid oral absorption for both insecticides and subsequent metabolism and distribution of the active oxon metabolites. Figure 14 illustrates the capability of the diazinon PBPK/PD model to simulate rodent dosimetry data from the open literature and the capability of the model to accommodate alternative exposure routes (Poet et ai, 2004). In these examples, the time course of diazinon in plasma and cholinesterase inhibition in tissues (i.e.. blood,... 

The effect of moxifloxacin on the QT interval has been studied in 20 healthy subjects who received either moxifloxacin 400 mg (route not specified, although mean time to maximum concentration was 2.3 hours, implying an oral dose) or placebo [72 ]. A pharmacokinetic-pharmacodyamic model estimated a 3.9-msec increase in the QTc interval for every 1 mg/1 increase in moxifloxacin concentration. The mean peak moxifloxacin concentration was 2.24 mg/1. An early increase in QTc interval reverted almost to baseline values at 5-6 hours after the dose, and then increased again and remained above the predose baseline for up to 48 hours after the dose. The authors attributed the fall in QTc interval at 5-6 hours to artifact. 

There is very limited data on the absorption, metabolism, and pharmacokinetics of orally or dermally administered BP in either humans or in animal models, and no published literature could be located on the metabolism of 4-MBP by any route of exposure. Available studies on BP are summarized below. 

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