The hepatic elimination is determined from intrinsic clearance, such as cellular water, neutral lipid, neutral phospho DAPT secretase molecular weight lipid, and microsomal binding. Some subscripts refer to active transport processes, such as P gp mediated transport, as well as other where Vmax and Km are the Michaelis Menten parameters of drug biotransformation measured in mice hepatic pooled microsomes, and NCYP450 is the amount of mice hepatic cytochrome P450. The conventional description of hepatic extraction ratio corresponds to for a well stirred liver model, where fumic is the fraction of drug unbound to hepatic microsomes which can be estimated as follows for a basic drugwhere Cmic is the microsomal protein concentration, and LogP is the octanolwater partition coefficient of the drug.

The mass balance equations of the WS model applied to Mechanistic Transport Based models We propose a transport based tissue model to mechan istically investigate drug distribution in non eliminating tissues expressing active transporters. Inhibitors,Modulators,Libraries This tissue model accounts for apparent passive diffusion and active transports of the drug at the blood tissue membrane. Since only limited transport related information is available within extra and intra cellular space of a tissue, it has been resumed by the transport occurring at the capillary membrane. This choice has the advantage to minimize the recourse to fitting procedures of transport related parameters that would have been required in a three sub compartmental tissue model.

Thus, we assigned the term apparent to the transport related parameters and divided the tissue in two well stirred compartments representing the vascular and extravascu lar tissues, separated by a capillary membrane where apparent diffusion and apparent active transports of the unbound drug occur. The fraction of drug unbound to tissue was calculated from the total tissue Inhibitors,Modulators,Libraries concentration CT estimated from the method developed by Rodgers and Rowland. Indeed, CT can be expressed Inhibitors,Modulators,Libraries in terms of the unbound concentration in intracellular and where fiw is the fractional tissue volume of intracellular water and few fractional tissue volume of extracellular Inhibitors,Modulators,Libraries water. We used published tissue specific data, and assumed that the tissue composition in protein is the same among rodent. The active transports include, but are not limited to, apparent P gp mediated efflux of the unbound drug from tissue to blood.

This general mechanistic transport based model can also account for additional efflux andor influx transporters. We first only consider the contribution of apparent passive diffusion and P gp mediated Inhibitors,Modulators,Libraries transport in both tissues, setting thus to 0 the terms CLin, OT and CLout, OT. The transport based tissue model can selleck chem MG132 also be used to investigate the involvement of additional transporters by setting to non zero values the parameters CLin, OT and CLout, OT.