Although epidermal growth factor (EGF) induces transient activation of Ras and the mitogen-activated protein kinase (MAPK) cascade in PC12 cells, whereas nerve growth factor (NGF) stimulates sustained activation, the basis for these contrasting responses is not known. We have developed a computer simulation of EGF-induced MAPK cascade activation, which provides quantitative evidence that feedback inhibition of the MAPK cascade is the most important factor in determining the duration of cascade activation. Hence, we propose that the observed quantitative differences in EGF and NGF signalling can be accounted for by differential feedback regulation of the MAPK cascade. ß 2000 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.

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ABSTRACT:Estimation of xenobiotic kinetics in humans frequently relies upon extrapolation from experimental data generated in animals. In an accompanying paper, we have presented a unique, generic, physiologically based pharmacokinetic model and described its application to the prediction of rat plasma pharmacokinetics from in vitro data alone. Here we demonstrate the application of the same model, parameterized for human physiology, to the estimation of plasma pharmacokinetics in humans and report a comparative evaluation against some recently published predictive methods that involve scaling from in vivo animal data. The model was parameterized through an optimization process, using a training set of in vivo data taken from the literature, and validated using a separate test set of published in vivo data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was 0.47 log unit. For the training set, more than 80% of the predicted values of a standardized measure of the area under the concentration-time curve were within 3-fold of the observed values; over 70% of the test set predictions were within the same margin. Furthermore, in terms of predicting human clearance for the test set, the model was found to match or exceed the performance of three published interspecies scaling methods, all of which showed a distinct bias toward overprediction. We conclude that the generic physiologically based pharmacokinetic model, as a means of integrating readily determined in vitro and/or in silico data, is potentially a powerful, cost-effective tool for predicting human xenobiotic kinetics in drug discovery and risk assessment.Physiologically based pharmacokinetic (PBPK) models are mathematical descriptions of the flow of blood throughout the body, developed for the simulation of xenobiotic absorption, distribution, and elimination. Such models have been used by scientists from a number of different disciplines who are interested in the simulation and prediction of exposure (Grass and Sinko, 2002;Leahy, 2003).The application of a generic form of a PBPK model to the prediction of xenobiotic plasma levels in rat following an intravenous dose has been reported in an accompanying publication (Brightman et al., 2006). Here we describe the work that we have done to parameterize the same PBPK model for humans and to assess the reliability of the model in estimating plasma levels of xenobiotics, where these values are known from experimentation. In addition, we draw comparisons with alternative methods for predicting human pharmacokinetic properties that involve extrapolation from experimental data generated in animals.Just as there are numerous published compound-specific PBPK models for the rat that use data derived from in vivo studies (Sugita et al., 1982;Igari et al., 1983;Tsuji et al., 1983;Bernareggi and Rowland, 1991;Kawai et al., 1994;Blakey et al., 1997), there are many examples of comparable PBPK models for humans that rely upon scaling f...

ABSTRACT:The routine assessment of xenobiotic in vivo kinetic behavior is currently dependent upon data obtained through animal experimentation, although in vitro surrogates for determining key absorption, distribution, metabolism, and elimination properties are available. Here we present a unique, generic, physiologically based pharmacokinetic (PBPK) model and demonstrate its application to the estimation of rat plasma pharmacokinetics, following intravenous dosing, from in vitro data alone. The model was parameterized through an optimization process, using a training set of in vivo data taken from the literature and validated using a separate test set of in vivo discovery compound data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was approximately 0.5 log unit. Around 70% of all the predicted values of a standardized measure of area under the concentration-time curve (AUC) were within 3-fold of the observed values, as were over 90% of the training set t 1/2 predictions and 60% of those for the test set; however, there was a tendency to overpredict t 1/2 for the test set compounds. The capability of the model to rank compounds according to a given criterion was also assessed: of the 25% of the test set compounds ranked by the model as having the largest values for AUC, 61% were correctly identified. These validation results lead us to conclude that the generic PBPK model is potentially a powerful and cost-effective tool for predicting the mammalian pharmacokinetics of a wide range of organic compounds, from readily available in vitro inputs only.Physiologically based pharmacokinetic (PBPK) models are mathematical descriptions of the flow of blood throughout the body, developed for the simulation of xenobiotic absorption, distribution, and elimination. The essential concepts were outlined over 60 years ago in a farsighted paper (Teorell, 1937) that presented many of the mathematical relationships required to simulate blood flow and tissue distribution.Simulation modeling ideas were developed further by Mapleson (1973), to explain the effect of anesthetics, and early attempts to apply the approach to drugs were published in the 1960s by Bellman et al. (1961). Probably the most important contributions in that period were made by Bischoff and Dedrick (1968), who demonstrated that PBPK models could be used for the a priori prediction of the pharmacokinetics of thiopental. During the following decades, developments were made by academics such as Rowland (Rowland, 1986), Sugiyama (Sugiyama and Ito, 1998), and Amidon (Yu and Amidon, 1999), as well as scientists working in the environmental health field, in particular Anderson and Clewell (Andersen et al., 2002). Recent reviews (Grass and Sinko, 2002;Leahy, 2003) have discussed the application of these approaches to the prediction of pharmacokinetics in drug discovery.It is of interest to us to apply the PBPK approach to the estimation of plasma levels in animals from in vitro d...

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