Determination of Mean Residence Time of Drug in Plasma and the Influence of the Initial Drug Elimination and Distribution on the Calculation of Pharmacokinetic Parameters

The equation for the calculation of mean residence time of drug in plasma, t(p), is obtained. It is shown that the previously suggested calculation of tp considerably overestimates the true value in most cases. It is suggested that due to the possible initial (before establishing the uniform drug mixing in plasma) fast elimination of drug, the commonly calculated total body clearance (Cl = D/AUC) may substantially overestimate the clearance in the linear range of elimination of well-stirred drug. This would result in the high in vivo Cl values that are not supported by the in vitro studies of drug metabolism and stability in tissues. It is shown that the mean residence time of drug in the body, volumes of distribution, oral bioavailability and distribution clearance estimated with the account of initial drug distribution and elimination, may substantially deviate from the values obtained by the traditional calculations. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:748-762, 2008