4-Week Toxicity and Toxicokinetic Oral Gavage Study with Polydatin in Rats

Objective: This study determined the toxicity and toxicokinetics of polydatin when administered via oral gavage to Sprague Dawley rats daily for 4 weeks. Background: Polydatin continues to be investigated as a potential therapy for a variety of human diseases. Methods: Male and female Crl:CD(SD) rats were assigned to five groups, and different doses (0, 300, 600, 1200, or 3000 mg/kg/day) of polydatin were administered via oral gavage once daily for 29 days at a dose volume of 10 mL/kg. Assessment of toxicity was based on mortality, clinical observations, food consumption, body weights, ophthalmic examinations, and clinical and anatomic pathology. Blood samples were collected for toxicokinetic evaluations. Results: All animals survived to the end of the study. Animals given polydatin at ?600 mg/kg/day exhibited lower mean body weight (?10% compared with control) and less gain in mean body weight, which correlated with decreased food consumption, compared to control rats. Several minor clinical chemistry findings were observed at ?600 mg/kg/day, but they were all of small magnitude, and were not considered adverse or toxicologically important. Polydatin related macroscopic findings included one animal with an enlarged cecum in the 1200 mg/kg/day group and 6 of 20 animals with enlarged cecums or colons in the 3000 mg/kg/day group. These findings were considered test article-related, although no microscopic correlate was present. In males given 1200 or 3000 mg/kg/day and females given 3000 mg/kg/day microscopic findings in the kidneys included tubular dilatation, hyaline droplets in the tubule cells (males only), erosion/ulceration of the transitional epithelium, acute pelvic inflammation (males only), and chronic active pelvic inflammation with hyperplasia of the transitional epithelium (females only). No marked sex differences were observed in polydatin Cmax and AUC0-24 values. No accumulation of polydatin was observed after multiple dosing. Conclusion: The only adverse test article-related finding noted in one female given 3000 mg/kg/day was chronic active pelvic inflammation and transitional cell hyperplasia. Based on these results, the no observed adverse effect level (NOAEL) is 1200 mg/kg/day for females and 3000 mg/kg/day for males.