Kinetic analysis of AUC-dependent saturable clearance of liposomes: mathematical description of AUC dependency.

The objective of this study was to examine the AUC dependency of saturable hepatic clearance (CLh) of liposomes and to postulate a mathematical model to describe the characteristics. The AUC dependency of saturable CLh was examined under intravenous rapid administration at various doses. The CLh increased with increasing blood concentration but decreased with the increase of AUC at each dose. In addition, the relationship between AUC and CLh was consistent with that observed in previously reported infusion studies. These experimental data confirm the AUC dependency of saturable CLh of liposomes. A mathematical model was developed for this AUC dependency. The decrease of CLh was described by the uptake amount (X) as follows: CLh = CLm(1-X/Xm), where CLm and Xm represent the maximum uptake clearance and the maximum uptake amount, respectively. The rate equation for uptake was analytically solved as CLh = X/AUC = Xm/AUC(1-exp(CLm/XmAUC)). Uptake clearance can be described by CLm, Xm, and AUC, and so uptake clearance is constant if AUC is constant. These experimental analyses and theoretical considerations show the validity of the AUC-dependent saturable CLh of liposomes.