Acute toxicity, 28-day repeated-dose toxicity and toxicokinetic study of timosaponin BII in rats

- Loose stool was observed in rats receiving a single oral dosage of 4000 mg/kg TBII.
- TBII at 540 mg/kg caused loose stool and changes in body weight and food consumption.
- Urinalysis showed reversible TBII-related toxic changes in rats at 540 mg/kg.
- Systematic exposure to TBII dose-dependently increased after 28-day treatment.
- The NOAEL for rats exposed orally to TBII for 28 days is proposed to be 180 mg/kg.

Timosaponin BII (TBII), a major steroidal saponin isolated from Anemarrhena asphodeloides Bge., displays a variety of promising pharmacological activities, such as neuroprotection, enhancement of learning and memory, vascular protection and inhibition of platelet aggregation; therefore, it has been developed as a pharmaceutical for prevention or treatment of dementia. Given the safety concerns surrounding timosaponins and the absence of studies on the safety of TBII, the potential toxicity of TBII was evaluated in toxicity and toxicokinetic studies in rats. In the acute oral toxicity study, loose stools were observed in rats receiving 4000 mg/kg, and the symptoms recovered within 1 day. In the 28-day repeated-dose oral toxicity and toxicokinetic study, rats receiving 540 mg/kg showed loose stools and a slight deceleration of body weight growth in both sexes, and the females also showed a slight decrease in food consumption. Moreover, urinalysis indicated reversible treatment-related toxicity in rats receiving 540 mg/kg. The toxicokinetic study demonstrated a dose-dependent increase in systematic exposure to TBII after 28 successive days of oral treatment with TBII. The accumulation coefficients of TBII were 4.35, 1.70 and 1.81, respectively, in rats that received 60, 180 and 540 mg/kg. The no-observed-adverse-effect level (NOAEL) is proposed to be 180 mg/kg.