Studies On The General Toxicity And Toxicokinetics Of Ailanthone

Ailanthone?AIL?has many bioactivities including antiplasmodial,anti-viral and anti-cancer.Our previous studies have proved that AIL targets p23 against castration-resistant prostate cancer with good drug-like properties.In this study,the preclinical safety evaluation of AIL was carried out through assays of acute toxicity,subacute toxicity and toxicokinetics in Kunming mice.The LD₅₀ for AIL was 27.25 mg/kg,and the severe pathological damages were observed mainly in liver and gastrointestinal tract.In subacute toxicity study,mice were gavaged at the dose levels of 2.5 mg/kg,5 mg/kg and 10 mg/kg for 28 days,and the satellite group of the highest dose level was scheduled for a 15-day recovery from toxic effects.Results indicated that,in the 10mg/kg dose group,the body weight of male mice decreased and a death case occurred,while unusual body weight increase and rare toxic response were observed in female mice.The biochemistry and histopathological analysis showed that AIL caused steatohepatitis,immune dysfunction,damage of gastrointestinal mucos and abnormal reproductive system.In addition,AIL also showed reversible hematotoxicity suppression at the dose of 10 mg/kg.Blood RBC,HGB,HCT and MCHC were significantly increased,while RDW-CV,PLT were decreased.After 15 day-recovery,the abnormal parameters were returned to the normal level,compared to the control group.To determine the relationship between the toxicity and dose/in vivo exposure of AIL,the concentrations of AIL in plasma and tissues were determined after a single dose administration of 15 mg/kg.AIL was widely distributed in tissues.Stomach was identified as the main target organ,followed by intestine and kidney.In summary,this study is the first time to investigate the general toxicity and toxicokinetics of AIL,which may be especially useful for further development.