Positive linear correlations WS Model The concentration time profiles of domperidone simu lated in tissues using the WS model are presented in Figure 5. Only tissues for which experimental data were available are shown. The WS model successfully simu lated the time concentration profile of domperidone jq1 in hepatic tissue, Inhibitors,Modulators,Libraries indicating that the drug disposition in the main eliminating organ was adequately characterized. However, the WS model tends to overestimate domper idone concentrations in heart and brain tissues, which is likely to be related to a Inhibitors,Modulators,Libraries poor estimation of tissue to plasma partition coefficients for these tissues. The most important over prediction of drug concentration is obtained in brain tissue. The predicted peak concentra tion in this tissue, regardless of the mice strain, was 8.

5 mgL, compared to a maximum measured concentration less than 0. 03 mgL and 0. 22 mgL, for WT mouse and KO Inhibitors,Modulators,Libraries mouse, respectively. As, by definition, this model is not suited to account for both active and passive transport mechanisms effect on drug distribution, a MTB model is applied to heart and brain tissues. MTB Models Accounting only for P gp Efflux Activity in Heart and Brain P gp has a protective function by limiting drug accumu lation into heart and brain tissues. Therefore, we applied the MTB model to these tissues, and the WS model to all other tissues. The PBPK simulation results are illustrated in Figure 6. While the simulated effect of P gp tends to be slightly lower than the observed one, the MTB model captures the peak Inhibitors,Modulators,Libraries concentration of domperidone for both mice strains in heart tissue.

These results suggest that the apparent diffusion, rather than active transport, is the main transport mechanism of drug distribution in heart tissue. The MTB model significantly improves the WS model results Inhibitors,Modulators,Libraries in brain tissue, but it still tends to overestimate domperidone terminal concentration. In light of the above results, we were tempted to consider involvement of additional efflux membrane transporters in domperidone distribu tion in brain tissue. We derived its efflux clearance CLout, O by keeping diffusion and P gp mediated efflux parameters identical to those used for the brain MTB model while varying Clout, OT parameter in order to fit simulated profiles to the available brain concentrations.

In this case, the simulated concentration time curves capture those terminal time points measured in brain tissue of both mice strains, but fail to reproduce the time point concentration at 2 min post dose. Alisertib FDA The trend of drug concentration profile in brain tissue simulated in the absence of P gp activity but in the presence of additional efflux transporter is now in accordance with in vivo data. When compared to the WS model simulations, these results suggest that the apparent passive and active transport mechanisms are limiting processes of drug distribution in brain tissue.