Bioenhancing effects of piperine and curcumin on triterpenoid pharmacokinetics and neurodegenerative metabolomes from Centella asiatica extract in beagle dogs

Abstract

Centell-S is a water-soluble extract of Centella asiatica containing more than 80% w/w triterpenoid glycosides. Madecassoside and asiaticoside are two major components of the extract and can be converted into active metabolites, triterpenic acids in large mammal species. In this study, the pharmacokinetic profiles and metabolomic changes generated by the bioactive triterpenoids of Centell-S alone, and in combination with the bioenhancers piperine and curcumin, were investigated in beagle dogs. The test substances were orally administered over multiple doses for 7 consecutive days. At day 1 and 7 after receiving the test compounds, the level of major bioactive triterpenoids and related metabolites were measured using triple quadrupole and high-resolution accurate mass orbitrap models of LCMS to determine pharmacokinetic and metabolomic profiles, respectively. Centell-S was well tolerated, alone and in all combination groups. The combination of Centell-S and piperine significantly increased (p < 0.05) the systemic exposure of madecassoside on day 1 and asiatic acid on day 7, by approximately 1.5 to 3.0-fold of C_max and AUC values as compared to the Centell-S alone, while the addition of curcumin did not provide a significant improvement. Several metabolomic changes were observed from pre-dose to 4 h post-dose, with some biomarkers of neurodegenerative diseases including L-glutamine, lysophosphatidylcholine (17:0), taurochenodeoxycholic acid, uric acid, stearic acid, palmitic acid, and lactic acid showing good correlation with the systemic exposure of the bioactive triterpenoids (asiatic acid). Thus, the combining of piperine to Centell-S exhibits the improvement of bioactive triterpenoids which are related to the biomarkers of neurodegenerative diseases. These promising results might be useful for the development of this standardised extract to become a more effective phytomedicine for neurodegenerative diseases.

Figure 1

Chemical structures of piperine, curcumin and the bioactive triterpenoids of Centella asiatica extract.

Figure 2

Plasma concentration–time profiles of major bioactive triterpenoids from Centella asiatica extract alone and in combination with curcumin and/or piperine.

Figure 3

The distribution of mass area in each plasma sample group: Centella asiatica (CTS) extract alone, in combination with curcumin (CTS_Cur), in combination with piperine (CTS_Pip) and in combination with both curcumin and piperine (CTS_Pip_Cur) in (a) positive mode and (b) negative mode. The PCA plot of metabolites from (c) positive mode and (d) negative mode of each plasma sample group.

Figure 4

Boxplots of the metabolite biomarkers that changed 4 h after administration of Centella asiatica (CTS) extract alone, in combination with curcumin (CTS_Cur), in combination with piperine (CTS_Pip) and in combination with both curcumin and piperine (CTS_Pip_Cur) in the positive mode of detection.

Figure 5

Boxplots of the metabolite biomarkers that changed 4 h after administration of Centella asiatica (CTS) extract alone, in combination with curcumin (CTS_Cur), in combination with piperine (CTS_Pip) and in combination with both curcumin and piperine (CTS_Pip_Cur) in the negative mode of detection.