PBPK models are developed to predict xenobiotic disposition throu

PBPK models are developed to predict xenobiotic disposition throughout a mammalian body. By characterizing the kinetic processes of the drug, it is possible to predict its distribution inside tissues, organs and fluids concerning of the body. The whole body PBPK model involving tissues and organs Inhibitors,Modulators,Libraries connected via the vascular system mimics the anatomical structure of the mammal being studied. Generally, tissue distribution of drugs can be represented either by the perfusion rate limited model, or the permeability rate limited model. The former assumes an instantaneous and homogenous drug distribution Inhibitors,Modulators,Libraries in tissues, whereas the latter represents the tissue as two or three well stirred compartments which are separated by a capillary andor cellular membrane where a permeability rate limited transfer occurs.

However, the membrane perme ability may not be the only factor contributing towards limitation of drug distribution within a tissue. The influx or efflux activity of ABC transporters can be another important factor Inhibitors,Modulators,Libraries involved in drug distribution and should be considered as such in PBPK modeling. In drug research and development, predicting drug disposi tion prior to in vivo studies is a major challenge. Within this context, the hypothesis driven strategy adopted here is to build a data Inhibitors,Modulators,Libraries independent model that minimizes recourse to data fitting and exploits in vitro data information. Indeed, the spirit of PBPK modeling is deeply rooted in the independence of the model building on the output data representing the process to be described.

It is based on the Inhibitors,Modulators,Libraries integration within a whole entity of drug specific character istics with a structural mode which can be more or less detailed in terms of tissues and organs to be included. As relevant knowledge of the physiological, morphological, and physicochemical data becomes available, the possibility exists for efficient use of limited data in order to reasonably describe the pharmacokinetics of specific compounds under a variety of conditions. With this in mind, the whole body PBPK model developed herein aims to shed light, prior to in vivo experiments, on drug distribution in tissues expressing P gp transporters. For this purpose, we adopt a step by step procedure which led us to the final PBPK model applied to mice, which accounts for the P gp mediated efflux transport in heart, and brain tissues.

We first use the WS model to represent the drug distribution in each tissue. Then, to account for both passive and active transports, a mechanistic transport based model is developed for heart and brain. In order to selleckbio estimate transport related parameters all the while minimizing data fitting, we developed a method to extrapolate in vitro measurements of drug permeability of P gp substrates through endothelial cells monolayers to the in vivo situation.

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