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

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