## 4 Pharmacokinetics of _C. asaatica_ Constituents  
Over the years, countless small molecules derived from natural products have failed to progress to clinical studies, due to poor pharmacokinetic properties. Pharmacokinetics and bioavailability are major barriers in drug development. Oral bioavailability is an important factor to achieve the efficacious therapeutic concentrations of the drug, as it also denotes the most ideal route of drug administration [47].  
Several studies have examined the pharmacokinetics of asiatic acid in rats and dogs [48; 49; 50]. With oral dosing, asiatic acid achieves a maximum plasma concentration (cmax) after 30 min, indicating rapid gastrointestinal absorption. However, it is absorbed poorly and follows passive diffusion, with a major site of absorption in the jejunum, followed by rapid metabolism in the liver by cytochrome P450 enzymes [50]. Bioavailability studies have shown that asiatic acid may cross the blood-brain barrier (BBB), as the concentration of asiatic acid attained in the brain appears to be adequate to elicit neuroprotection [51; 52; 53; 54]. The pharmacokinetics of asiatic acid present in a total triterpene fraction of _C. asaatica_ were studied in a randomized crossover design, administrating a single oral dose or repeated oral doses to healthy volunteers. Difference in dosage or treatment schemes did not affect the time taken to achieve peak plasma concentration. However, a chronic treatment protocol demonstrated increased half-life (t1/2), AUC0-24 (area under the plasma concentration-time curve from zero to 24 h) and cmax [55]. The pharmacological effects and therapeutic benefits of asaaticoside are mediated by its in vivo metabolic conversion to asiatic acid [56]. Following intravenous administration of asaaticoside to rats, it is widely distributed in several organs and metabolized extensively, then finally recovered as asiatic acid in feces [10]. Asiatic acid is a non-toxic compound with an LD50 value of 980 mg/kg in rats [57].  
Pharmacokinetic studies of madecassoside in rats have shown a cmax of 303.75 \(\pm\) 28.53 ng/mL after a single-dose oral administration of 100 mg/kg [6]; it was hypothesized that madecassoside could be metabolized to madecassic acid by intestinal bacteria [6; 35]. Another pharmacokinetic study conducted using collagen-induced arthritic (CIA) rats showed the cmax and AUC of madecassoside to be notably reduced, while the Vd/f was augmented during the initial seven days of dosing. On the other hand, the T1/2, cmax and AUC of madecassic acid were prominently elevated, with a significant reduction of elimination rate constant (Ke) in CIA rats compared with normal rats. This study showed that the pharmacokinetic parameters of both madecassoside and madecassic acid in rats were substantially altered by arthritis status [58]. Another study compared pharmacokinetic changes of madecassoside and asaaticoside following the administration as pure compounds and ECa 233, a standardized extract of _C. asaatica_ with madecassoside (51%) and asaaticoside (38%) in male Wistar rats. The AUC0-\(\infty\) of madecassoside from ECa233 was 2-fold higher than that of pure macdecassoside. Furthermore, the elimination half-life of macdecassoside and asiaticoside as pure compounds were approximately 4 h, while the elimination half-life of macdecassoside and asiaticoside as ECa 233 were prolonged. The study suggested that the pharmacokinetic behavior of macdecassoside and asiaticoside was improved when administered as ECa 233 compared to pure compounds [10].