Pharmacokinetic modeling of the in vivo fate of long-circulating liposomes in rats.

Over the past decade, long-circulating liposomes have successfully been employed for the purpose of targeting a variety of drugs to sites of pathology in the body. Besides target-selective accumulation, encapsulation in long-circulating liposomes can dramatically improve the pharmacokinetics of the drug. Since the pharmacokinetic behavior of liposomal agents is very different from free drugs, assessing this is not straightforward. An important difference regards the early phase of the plasma concentration-time profile of a liposome, which is generally determined by elimination due to phagocytosis by liver and spleen macrophages. This process of liposome clearance appears to be dose dependent and can be saturated. When either plotted against time or lipid dose, the liposome uptake curves by liver and spleen appear to be logarithmic and gradually reach a maximum value. The phenomenon of uptake saturation may be explained by limited pools of opsonic plasma proteins that are able to interact with the injected amount of liposomes in the circulation or by a limited amount of phagocyte receptors that can recognize opsonized liposomes in the blood. We propose a mathematical model describing dose-and time-dependent liposome distribution and elimination in the rat body. The aim of the model is to introduce a limited set of parameters that are time-and dose-independent and therefore characteristic for a given liposomal formulation and to fit these parameters to liposome biodistribution data obtained in rats. This set of parameters includes a maximum liver and spleen uptake, and also includes constants that describe the speed by which a given liposome formulation is taken up. Although difficult to monitor, we also aim at introducing a body compartment in the model to describe the late phase of liposome elimination from the circulation. Such pharmacokinetic modeling may be helpful with assessing the in vivo fate of a liposomally encapsulated drug and evaluating the role of the lipid dose, without the need of extensive animal studies.