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 ultra-performance liquid chromatography-tandem mass spectrometry 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 (C0/Dose) and systemic exposure (AUC(0-∞)/Dose) along with a prolonged elimination half-life (t1/2) compared with 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 uptake, whereas 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 reticuloendothelial system-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. SIGNIFICANT STATEMENT: This study established an ultra-performance liquid chromatography-tandem mass spectrometry method for simultaneous determination of free and total paclitaxel and provided a descriptive characterization of formulation-associated differences in pharmacokinetics, tissue distribution, and excretion. These findings offer a pharmacokinetic reference that may inform the rational design and evaluation of lipid-based nanomedicines in future studies.