Pharmacokinetics, Tissue Distribution and Excretion Study of Fluoresceinlabeled PS916 in Rats

Background: PS916, chitosan derivative with shown activities in atherosclerotic and fatty liver, is being investigated as an anti-atherosclerotic agent in clinical trials in China. Methods: Fluorescein-labeled PS916 (PS916-FTC) was prepared by the reaction with fluorescein isothiocyanate. The pharmacokinetics and bio-disposition of PS916-FTC were studied in rats after oral or intravenous administration. Results: Analysis of the plasma, urine, fecal and tissue samples collected at intervals up to 72 h revealed that PS916-FTC exhibited moderate volume of distribution (Vss, 0.650~0.748 L/kg), and low clearance (60.9~107 mL/h/kg) after intravenous administration. The pharmacokinetics of PS916-FTC was characterized by low bioavailability (8.40%) after oral administration. The average accumulation ratio for PS916-FTC exposure after steady-state administration was 1.04. A two-compartmental pharmacokinetics model was employed. The urinary route was the major pathway (54.4%), and the fecal route was a minor pathway (6.29%) for PS916-FTC elimination after intravenous administration; the fecal route was the major pathway (79.0%) for PS916-FTC elimination after oral administration. Conclusion: PS916-FTC was widely distributed to most tissues in rats; relatively high levels of PS916-FTC in kidney and liver were observed after intravenous or oral administration. These findings supported the understanding of pharmacokinetics and bio-disposition of PS916 in rats and provide relevant information for future design of clinical studies. Highlights: 1) Fluorescein-labeled PS916 was successfully synthesized. 2) A rapid and sensitive analytical method of PS916-FTC was validated. 3) The pharmacokinetic of PS916-FTC in rats was investigated. 4) The bio-distribution of PS916-FTC in rats was investigated.