The influence of hepatic transport on the distribution volumes and mean residence time of drug in the body and the accuracy of estimating these parameters by the traditional pharmacokinetic calculations

The influence of hepatic uptake and efflux, which includes passive diffusion and transporter‐mediated component, on drug distribution volumes [steady‐state volume of distribution (Vss) and terminal volume of distribution (Vβ)], mean residence time (MRT), clearance, and terminal half‐life is considered using a simplified physiologically based pharmacokinetic model. To account for hepatic uptake, liver is treated as two‐compartmental unit with drug transfer from extracellular water into hepatocytes. The exactly calculated distribution volumes and MRT are compared with that obtained by the traditional equations based on the assumption of central elimination. It was found that Vss may increase more than 10‐fold and Vβ more than 100‐fold due to the contribution of transporter‐mediated uptake. The terminal half‐life may be substantially shortened (more than 100‐fold) due to transporters. It may also decrease significantly due to the increase of intrinsic hepatic clearance (CLint), whereas hepatic clearance has already reached saturation (and stays close to the possible maximum value). It is shown that in case of transporter‐mediated uptake of compound into hepatocytes, in the absence of efflux and passive diffusion (unidirectional uptake), hepatic clearance is independent of CLint and is determined by hepatic blood flow and uptake rate constant. The effects of transporter‐mediated uptake are mostly pronounced for hydrophilic acidic compounds and moderately lipophilic neutral compounds. For basic compounds and lipophilic neutral compounds the change of distribution volumes due to transporters is rather unlikely. It was found that the traditional equations provide very accurate values of Vss, Vβ, and MRT in the absence of transporter action even for very low rates of passive diffusion. On the other hand, the traditional equations fail to provide the correct values of these parameters when the increase of distribution volumes due to transporters takes place, and actually yield the values substantially smaller than the true ones (up to an order of magnitude for Vss and MRT, and three orders of magnitude for Vβ). © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:5031-5047, 2011