Journal of Pharmaceutical Investigation最新文献

Purpose: Pharmacokinetic (PK) data for levamisole, an important immunostimulant and antiparasitic agent, were identified in 18 species providing sufficient PK data following oral (PO) and/or intravenous (IV) administration for assessment and comparison.

Methods: Pharmacokinetic parameters were sought in all species for traditional allometric assessment. Among these, 2 bird and 6 mammalian species provided sufficient data for joint modeling using traditional compartmental PK and minimal physiologically-based pharmacokinetic (mPBPK) methods.

Results: Simple allometric scaling was first used examine clearance (CL), steady-state volume of distribution (V _ss ), absorption rate constant (k _a ), and bioavailability (F) in relation to body weight (BW) across species. The V _ss correlated well with BW (Parameter = α·BW ^b ) with b = 0.89 (R² = 0.81) whereas CL (b = 0.26, R² = 0.46), k _a (b = 0.25, R² = 0.14), and F (b = 0.08, R² = 0.70) showed weaker correlations with ducks appearing as outliers for CL. Biexponential PK profiles were adequately captured using an allometric two-compartment model (2CM). Joint fitting of IV PK data from 8 species to a generalized mPBPK model, incorporating unified distribution parameters (e.g., tissue partition coefficient K _p and fractional distribution parameter f _d ), yielded good performance across species. The mPBPK model assuming high tissue permeability and species-specific K _p values for pig and chicken (K _{p, pig} and K _{p, chicken} ) best described the observed profiles. Oral bioavailability(F) was highly consistent across all species (50-80%), with the exception of goats.

Conclusion: This study demonstrates that levamisole with rapid absorption and extensive metabolism exhibits largely consistent PK properties across species. Minimal PBPK modeling offers advantageous comparison of interspecies determinants of levamisole PK.

Supplementary information: The online version contains supplementary material available at 10.1007/s40005-025-00770-6.

Purpose: Poly(ethylene glycol) (PEG), a synthetic polymer known for its hydrophilicity and biocompatibility, has long been used in drug delivery systems to prevent non-specific protein adsorption and to extend the blood circulation time of drug carriers and protein drugs. However, PEG has several drawbacks including poor stability, accumulated toxicity, and immunogenicity induced by repeated injections. Recently, zwitterionic polymers, known for their super-hydrophilic and antifouling properties, have been considered excellent alternatives to PEG. In this study, we synthesized a new zwitterionic polymer from biocompatible sodium alginate and lysine.

Methods: Sodium alginate (Alg) was conjugated with lysine (Lys) using the EDC/sulfo-NHS chemistry to form a zwitterionic alginate derivative (Alg-Lys). The biocompatibility was evaluated using in vitro cellular assays and in vivo animal studies. After further conjugation of zwitterionic near-infrared (NIR) fluorescent dye ZW800, an in vivo NIR fluorescence imaging study was conducted to evaluate the ability of Alg-Lys to enhance blood circulation time.

Results: Characterization of Alg-Lys showed that the carboxylic acid groups in Alg were completely replaced by Lys molecules. No cytotoxic effects were observed in the in vitro cytotoxicity tests of Alg-Lys-treated cancer cells and normal cells. Serum biochemical analysis confirmed the biocompatibility of Alg-Lys. ZW800-conjugated Alg-Lys exhibited strong fluorescence signals throughout the body 24 h after intravenous injection, whereas ZW800-conjugated Alg was rapidly removed from the body.

Conclusion: The zwitterionic alginate derivative showed potential utility as a new delivery platform for imaging agents and drugs.