To appreciate the reliability of the knowledge that the model provides in terms of elucidating the impact of the modulation of P gp activity on drug distribution, we had access to WT and KO tissue concentrations of domper idone, an antiemetic drug associated with cardiac toxicity. The choice of this drug model was motivated by previous in vitro results, which suggested that domperidone could Pazopanib structure be highly transported by P gp. While this data set cannot be considered rich enough to validate the developed PBPK model, it can at least show that, the model simulations lie within realistic values by capturing points in the main strategic regions of the tissue concentration profiles, namely at the maximum concentration and the elimination phase.
Methods Structure of the PBPK model The present investigation Inhibitors,Modulators,Libraries focuses on P gp substrate dis tribution Inhibitors,Modulators,Libraries in heart and brain tissue where this transporter has a protective function. Our whole body PBPK model included these tissues as well as core tissues, organs and fluids, namely liver, arterial and venous blood, along with the adipose tissue because of its involvement in the disposition of lipophilic drugs. To make the model readily usable for subsequent updates and future experimental data, we also included bone, gut, lung, kidneys, muscle skin and spleen in the PBPK structure. The PBPK model is mathematically formulated as a set of ordinary differential equations of mass balance that represents the time dependent variation of the drug concentration in each tissue. We systematically Inhibitors,Modulators,Libraries performed an overall mass balance of the whole body PBPK model to assure that mass conservation laws are respected.
Tissue distribution models transporters such as influx transporters and additional efflux transporters. Well stirred model At this first step of Inhibitors,Modulators,Libraries model development, the whole body PBPK model Inhibitors,Modulators,Libraries is based on perfusion selleck Paclitaxel limited model of disposition. The uptake rate of the drug into tissues is limited by the flow rate to tissue rather than the diffusion rate across cell membranes. In this case, the unbound concentration of drug in tissue is in equilibrium with the unbound drug in the outcoming blood. The application of a WS model requires the tissue to plasma partition coefficient of each tissue included in the PBPK model as input parameters. By definition, these partition coefficients were calculated as The parameters used in the equations presented in this section refer to concentration, volume, blood flow to tissue, tissueplasma partition coefficient. bloodplasma ratio, unbound fraction of drug, clearance, and permeability surface area product.