Absorption, distribution, metabolism model validation

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. 

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,... 

Since Intestinal absorption and Intestinal and hepatic first-pass metabolism are the major processes limiting bloavallablllty, the majority of the methods described below will focus on appropriate models for these processes. Nevertheless, It should be emphasized that other barriers, notably the blood-brain barrier (BBB) and virtually all organ-related membrane barriers, also need to be considered when Investigating the distribution of a compound throughout the body and ultimately Its tissue bloavallablllty. A recent study by the European Centre for the Validation of Alternative Methods (ECVAM) compared In vitro BBB methods and characterized several models In relation to In vivo studies Immortalized BBB-derlved endothelial cell lines (SV-ARBEC, MBEC4), non-BBB-derlved cell lines (MDCK, Caco-2, ECV-C6), and primary cells derived from BBB. In all cases, the correlations between In vitro and In vivo assays were low [36], and, moreover, most In vitro methods lacked at least some of the features of the In vivo barrier [37, 38]. Therefore, animal studies will continue to play a major role In studies of the BBB. 

---