Liposomal encapsulation redirects the in vivo disposition of paclitaxel: a comparative pharmacokinetic, tissue distribution, and excretion study in rats

Paclitaxel (PTX) is a potent chemotherapeutic agent for solid malignancies. However, its poor aqueous solubility necessitates toxic solubilizers in conventional formulations, which lead to adverse reactions and unpredictable pharmacokinetics. Liposomal encapsulation offers a biocompatible alternative to overcome these limitations. In this study, a sensitive ultrafiltration coupled with UPLC-MS/MS method was developed and validated for the simultaneous determination of free and total PTX in biological samples. This method was applied to compare the pharmacokinetic behavior of liposomal PTX (PTX-Lip) and conventional PTX injection in rats. Despite receiving a double dose (10 mg/kg), rats treated with PTX-Lip exhibited significantly lower dose-normalized initial concentration (C 0 /Dose) and systemic exposure (AUC (0-∞) /Dose) along with a prolonged elimination half-life (t 1/2 ) compared to the conventional formulation (5 mg/kg), indicating sustained release. Tissue distribution studies revealed extensive and persistent accumulation of PTX-Lip in the spleen and liver, consistent with reticuloendothelial system (RES) uptake, while distribution to other tissues was reduced. Excretion profiling demonstrated a fundamental shift in clearance pathways, from combined renal/hepatobiliary elimination for conventional PTX to predominantly hepatobiliary fecal excretion for PTX-Lip, with cumulative fecal recovery reaching 39.27% of the dose, a 2.4-fold increase over the conventional group (16.50%). Collectively, these findings illustrate how liposomal encapsulation modifies the in vivo disposition of PTX through RES-mediated sequestration, controlled drug release, and rerouted elimination. These descriptive observations, generated in healthy rats without pharmacodynamic or efficacy endpoints, provide a pharmacokinetic reference for the rational design of liposomal nanomedicines. However, these findings should be interpreted as a baseline pharmacokinetic characterization rather than as evidence of therapeutic benefit, and they are intended to generate hypotheses for validation in appropriate disease models with efficacy and safety endpoints.