Comparative Pharmacokinetic–Pharmacodynamic Evaluation of L-Theanine and L-Leucine Polymeric Nanoparticles in a Paracetamol-Induced Hepatic Injury Model

Background: Polymeric nanoparticle systems can modify the disposition and release characteristics of bioactive molecules and may improve their biological performance. The present work compared the in-vivo pharmacokinetic and hepatoprotective responses of optimized L-theanine- and L-leucine-loaded polymeric nanoparticles. Methods: Optimized formulations LT-SE-PN4 and LL-SE-PN4, prepared by the solvent evaporation approach, were selected for in-vivo evaluation. Their reported particle sizes were 127.21 ± 1.11 nm and 126.11 ± 1.09 nm, respectively, with entrapment efficiencies of 85.17 ± 0.30% and 81.37 ± 0.80%. Pharmacokinetic profiles were assessed following oral administration in albino rats. Hepatic effects were evaluated using serum AST, ALT, ALP and bilirubin, absolute liver weight and histopathological examination in a paracetamol-associated hepatic injury model. Results: LT-SE-PN4 produced a Cmax of 1.54 ± 0.42 µg/mL at 4 ± 0.08 h, whereas LL-SE-PN4 produced a Cmax of 2.98 ± 0.74 µg/mL at 2 ± 0.06 h. Reported AUC0–24 values were 22.36 ± 2.21 and 41.56 ± 2.78 µg/mL·h, with relative bioavailability values of 319.92% and 320.91%, respectively. Disease-control animals showed increased AST, ALT, ALP, bilirubin and absolute liver weight. Both nanoparticle-treated groups showed biochemical values closer to the normal-control group and comparatively preserved liver histology. Conclusion: The present work derived in-vivo findings demonstrate a consistent association between nanoparticle administration, altered systemic exposure and improved biochemical and histological indices in the experimental hepatic injury model. The findings support further controlled pharmacokinetic, mechanistic, toxicological and translational studies of these formulations. Keywords: L-theanine; L-leucine; polymeric nanoparticles; pharmacokinetics; hepatoprotection; paracetamol; liver injury; bioavailability.