Introduction

Asiaticoside（AS）, a pentacyclic triterpenoid saponin derived from C. asiatica, has a variety of pharmacological effects, including anti-inflammatory, antidepressant, and hepatoprotection, neuroprotection, wound healing, and anti-tumor effects [1]. Up to now, many scholars have investigated the pharmacological mechanisms and pharmacokinetics of AS. They pointed that asiaticoside has various pharmacological activities and has great potential to be developed as a new drug. In He et al.’s study, they reviewed the safety and pharmacokinetics of asiaticoside, as well as the pharmacological activities and mechanisms of action. The activities involved in the pharmacological properties of asiaticoside are illustrated in Figure 1.[2]

Safety of asiaticoside

In Southeast Asia, people ingest C. asiatica with vegetable and fruit juice, which supports the safety of this plant for human consumption. Simultaneously, several researchers have verified the safety of AS for human use. In 2012, Sampath et al. demonstrated the safety of AS and pointed that the lethal dose (LD₅₀) of asiaticoside is over 2000 mg/kg by acute oral administration. The physiological changes were observed in mice treated with 1000 mg/kg by sub-chronic oral administration[3]. In 2021, two studies demonstrated good tolerability to asiaticoside in animals and humans again. Given that AS has minimal interaction potential with respect to cytochrome P450 (CYP) isozymes, it is unlikely to interact with other drugs. Therefore, asiaticoside could be considered safe for various therapeutic approaches. However, Winitthana et al. found that AS had a mild inhibition effect on CYP2C19 and CYP3A4, indicating that some drug interactions might exist [4]. As these two studies both were in vitro studies, in vivo and clinical studies are necessary to further confirm the safety of asiaticoside.

Pharmacokinetics of asiaticoside

Zhu et al. indicated that the degradation of AS in rats occurred through first-order reactions . Specifically, following a single caudal vein injection of AS (40 mg/kg), the values of the peak concentration (C_max), half-life (T_1/2), area under the concentration/time curve (AUC_0–t), and (T_max) were 3347.9 ± 786.9 ng/mL, 23.4 ± 9.6 min, 81,443.67 ± 57,156.81 ng/(mL· min), and 5 min, respectively. When AS was administrated orally in rats, the C_max, T_1/2, AUC_0–t, and T_max were 658.17 ± 597.56 μg/L, 4.20 ± 0.91 h, 1937.19 ± 464.40 μg h/L, and 0.62 ± 0.79 h, respectively [5]. Previous studies have demonstrated that dogs have similar gastrointestinal anatomy and physiology to humans. Accordingly, dogs are often used for safety and pharmacokinetic studies. In 2012, Liu et al. orally administered AS (60 mg/kg) to dogs and found the corresponding values of C_max, T_1/2, AUC_0–t, and T_max to be 47.07 ± 15.36 ng/mL, 1.82 ± 0.12 h, 128.67 ± 26.23 ng min/h, and 1.44 ± 0.53 h, respectively [6]. According to these data, we can see that asiaticoside has a longer elimination half-life in dogs than in rats. Meanwhile, Hengjumrut et al. pointed out that the absolute bioavailability of asiaticoside was very low, i.e., 1.86%, which is consistent with a previous study by Liu et al. conducted in 2010 [5,7]. This may related to the incomplete absorption and excretion of absorbed AS, given that it is not highly water-soluble (Soe et al., 2020). ECa 233 is a standardized and commercial extract of C. asiatica containing more than 80% w/w triterpenoid glycosides, with a constant ratio of MS and AS (1.5 ± 0.5:1). Several researchers pointed that the pharmacokinetic parameters of ECa 233, including AUC_0–t, T_1/2, and C_max, were significantly higher than those observed for pure AS. This could be related to the action of centellasaponin as a bioenhancer in ECa 233 [5]. Interestingly, in vivo interconversion between MS and AS was observed after oral and intravenous dosing of the individual compounds in both rats and beagles, and the percent conversion of asiaticoside to MS after administration was higher than that in the opposite direction[5]. Further research is needed to explore fully the mechanisms associated with this phenomenon. In a tissue distribution study in rats, asiaticoside was rapidly distributed to various organs including the liver, kidney, heart, spleen, lung, stomach, skin, and brain within 1 h after administration of AS or ECa 233, and the highest concentrations were observed in the spleen. The superior lipophilicity of AS might facilitate its distribution in lipophilic tissues and internal organs, which could indirectly account for its high blood-brain barrier (BBB) permeability. Meanwhile, asiaticoside does not appear to have any harmful effects with respect to the BBB, which indicates that it has neuroprotective potential.[2]

Grimaldi et al. suggested that an enzyme (β-glycosidase) produced by glycoside-hydrolyzing intestinal bacteria could hydrolyze asiaticoside to asiatic acid. However, Jeong et al. found no asiatic acid in plasma samples and other tissues in rats. Boonyarattanasoonthorn et al. found asiatic acid to be the main metabolite in the plasma of dogs after oral administration of ECa 233 [8]. This was conffrmed in clinical research. Further studies on the metabolism and excretion of AS revealed that the unchanged form of asiaticoside in plasma was primarily eliminated via urine, while the metabolite asiatic acid was primarily eliminated via feces after the oral administration of ECa 233 in humans . However, intravenous administration of asiaticoside led to abundant asiatic acid in the feces of rats but not beagles [5,8].

Conclusion

To sum up, asiaticoside has great potential to be developed as a new drug because of its multiple pharmacological activities and good safety. The current trend of development of asiaticoside is the use of structural modifications to obtain derivatives with higher bioavailability. Accordingly, future research should develop several of derivatives by structural modifications, including methylation, acylation, and glycoside modiffcations, to improve the bioavailability of AS. Future research should focus on improving its bioavailability and conducting clinical assessment.[2]

References

[1] Tan SC, Bhattamisra SK, Chellappan DK, Candasamy M. Actions and Therapeutic Potential of Madecassoside and Other Major Constituents of Centella asiatica: A Review. Applied Sciences. 2021; 11(18):8475.

[2] He Z, Hu Y, Niu Z, et al. A review of pharmacokinetic and pharmacological properties of asiaticoside, a major active constituent of Centella asiatica (L.) Urb. J Ethnopharmacol. 2023;302(Pt A):115865.

[3] Sampath U. . Acute and sub-chronic oral toxicity of asiaticoside to mice. Int. J. Eng. Sci. Technol. 2012;4:4247–4252.

[4] Winitthana T, Niwattisaiwong N, Patarapanich C, Tantisira MH, Lawanprasert S. In vitro inhibitory effects of asiaticoside and madecassoside on human cytochrome P450. Toxicol. Vitro 2011;25:890–896.

[5] Hengjumrut P, Anukunwithaya T, Tantisira MH, Tantisira B, Khemawoot P. Comparative pharmacokinetics between madecassoside and asiaticoside presented in a standardised extract of Centella asiatica, ECa 233 and their respective pure compound given separately in rats. Xenobiotica. 2018;48(1):18-27.

[6] Liu S , Ju W , Zhou L ,et al.Analysis of Asiaticoside in Beagle Dog Plasma by Liquid Chromatography/Electrospray Ionization Tandem Mass Spectrometry and its Application to Pharmacokinetic Studies.[J].Current Pharmaceutical Analysis, 2011;7(2):95-100.

[7] Liu S J , Liu Z X , Ju W Z ,et al.Determination of Asiaticoside in Rat Plasma by LC–MS–MS and Its Application to Pharmacokinetics Studies[J].Chromatographia, 2010, 72(s9-10):821-825.

[8] Boonyarattanasoonthorn T, Kijtawornrat A, Songvut P, Nuengchamnong N, Buranasudja V, Khemawoot P. Increase water solubility of Centella asiatica extract by indigenous bioenhancers could improve oral bioavailability and disposition kinetics of triterpenoid glycosides in beagle dogs. Sci Rep. 2022;12(1):2909.