# The Potential Role of Timosaponin-AIII in Cancer Prevention and Treatment
## 3 Pharmacokine Profiles of TSAIII  
Pharmacokinetic studies have exhibited a crucial role in novel drug development. The detection of TSAIII in animal blood plasma after the oral administration of TSAIII or TSAIII-containing formulae has been performed. After the oral administration of free TSAIII (6.8 mg/kg) in healthy male SD rats, the Cmax, Tmax, AUC0-t, and T1/2 of TSAIII were 18.2 \(\pm\) 3.1 ng/mL, 2.3 \(\pm\) 0.57 h, 150.5 \(\pm\) 29.2 ng\(\cdot\)h/mL, and 4.9 \(\pm\) 2.0 h, respectively [25]. Another study reported that the values of T1/2, Cmax, and AUC were 2.74 \(\pm\) 1.68 h, 105.7 \(\pm\) 14.9 ng/mL, and 921.8 \(\pm\) 289.0 ng\(\cdot\)h/mL after the intragrasidal administration of TSAIII (25 mg/kg) in male SD rats [26]. Comparably, the values of these were 15.1 \(\pm\) 2.3 h, 77.28 \(\pm\) 21.47 ng/mL, and 916.61 \(\pm\) 208.43 ng\(\cdot\)h/mL after the intragrasidal administration of sarsasapogenin (25 mg/kg) [27]. Interestingly, these parameters for TSAIII could be 22.2 \(\pm\) 6.5 ng/mL, 3.15 \(\pm\) 0.62 h, 206.0 \(\pm\) 45.1 ng\(\cdot\)h/mL, and 9.9 \(\pm\) 2.8 h, respectively, after the oral administration of Zhimu/Baithe formula (containing 6.4 mg/kg TSAIII). The improved pharmacokinetic profiles might be associated with the increased biotransformation of TSAIII and synergistic effects [25]. After the oral administration of the saponin extract from _R Rhizoma anenarrhenae_, eight saponins were detected in the rat plasma. The pharmacokinetic profiles showed that TSAIII had the highest values of Tmax (7.85 h) and t1/2 (9.77 h). These suggested that TSAIII had a long body residence time and slow excretion [28]. Another study reported that after an oral administration of the 7 g/kg Zhimu/Bai formula, the level of TSAIII in the portal vein plasma and the systemic plasma in male Wistar rats was 1656.7 \(\pm\) 121.1 ng/mL/h and 650.5 \(\pm\) 45.2 ng/mL/h, respectively, indicating 60.7% of the  
Figure 2: The biotransformation of TSAIII: the transformation of TSBII into TSAIII could be regulated by \(\upbeta\)-D-glycosidase, and TSAIII could be further transformed into sarsasapogenin by removing the sugar chain at the C-3 position. -liver extraction rate and the dramatic liver first-pass effect. The values of Cmax, Tmax, and t1/2 were 5085.3 \(\pm\) 1581.5 ng/mL, 6 h, and 12.1 h, respectively. These suggested the comparable possibility of liver accumulation in TSAIII [18]. It has also been reported that Cmax, Tmax, and T1/2 of TSAIII were 94.4 \(\pm\) 3.8 ng/mL, 336.0 \(\pm\) 53.7 min, and 211.8 \(\pm\) 98.8 min after the oral administration of the Zhimu/Bai formula (10 g/kg, containing 19.2 mg/kg of TSAIII) in male SD rats. In the other group, these values were 84.3 \(\pm\) 8.6 ng/mL, 312 \(\pm\) 65.7 min, and 104.2 \(\pm\) 10.3 min after the oral administration of the Zhimu extract (10 g/kg, containing 18.7 mg/kg of TSAIII) [29]. The metabolites of TSAIII, including deglycosylated, glycosylated, and hydroxylated products, were identified, and these could be detected in the heart, urine, and feces. Only the parent form was detected in the plasma, liver, and kidney [30]. Another study reported that 19 metabolites were detected and identified from the rat plasma, bile, urine, and feces after a single oral dose of 400 mg/kg of TSAIII. Consistently, TSAIII underwent deglycosylation, oxidation, dehydrogenation, F-ring cleavage, and isotype reactions [31]. Salt processing, as a traditional processing method for Chinese herbs, has been reported to increase the content of TSAIII due to its increased transformation from TSBII. The AUC and Cmax of TSAIII after the oral administration of extracts of the unprocessed _A. rhizoma_ were 16.5 \(\upmu\)g-h/L and 4.5 \(\upmu\)g/L, respectively. However, these values decreased to 7.2 \(\upmu\)g-h/L and 2.18 \(\upmu\)g/L, respectively, after the oral administration of the processed samples. The explanation for these discrepancies in the pharmacokinetic parameters of TSAIII is complex. For example, salt processing could increase the metabolism and excretion of TSAIII [32].