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 (CL(h)) of liposomes and to postulate a mathematical model to describe the characteristics. The AUC dependency of saturable CL(h) was examined wider intravenous rapid administration at various doses. The CL(h) increased with increasing blood concentration but decreased with the increase of AUC at each dose. In addition, the relationship between AUC and CLA(h) was consistent with that observed in previously reported infusion studies. These experimental data confirm the AUC dependency of saturable CL(h) of liposomes. A mathematical model was developed for this, AUC dependency. 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 AUC is constant. These experimental analyses and theoretical considerations show the validity of the AUC-dependent saturable CL(h) of liposomes.