Inhibitory effect of asiaticoside and madecassoside on human cytochrome P450

Abstract

Asiaticoside and madecassoside, the triterpenoid compounds found in Centella asiatica (Linn.) Urban, are the major constituents in the standardized extract of C. asiatica (ECa233). Both compounds possess several interesting pharmacological effects. To obtain the preliminary drug interaction data, the aim of this study was to investigate inhibitory effects and types of inhibition of asiaticoside and madecassoside on human CYPs by using recombinant human CYPs in an in vitro study. This study included 3 parts: IC50 determination of asiaticoside and madecassoside on human CYP, assessment of mechanism-based inhibition and determination of the type of inhibition using enzyme kinetic study. For IC50 determination, asiaticoside inhibited CYP2C19 (IC50 = 412.68 µM) and CYP3A4 (IC50 = 343.35 µM). Madecassoside inhibited CYP2C19 (IC50 = 539.04 µM) and CYP3A4 (IC50 = 453.32 µM). Both asiaticoside and madecassoside did not affect CYP1A2, CYP2C9 and CYP2D6 (IC50>1,000 µM). Inhibition of asiaticoside on CYP2E1 was not observed at the concentration up to 200 µM while madecassoside did not affect CYP2E1 (IC50>1,000 µM). As asiaticoside and madecassoside demonstrated inhibitory effects on CYP2C19 and CYP3A4, types of inhibition of both CYPs were performed. In the mechanism-based inhibition study, madecassoside was shown to probably be a mechanism-based inhibitor of CYP2C19 and CYP3A4. Asiaticoside which was limited by its solubility, assessment of its mechanism-based inhibition potential could not be achieved. To determine the type of reversible inhibition, asiaticoside exhibited a pattern of noncompetitive inhibition of CYP2C19 (Ki = 588 µM) and CYP3A4 (Ki = 769 µM). Madecassoside also exhibited a pattern of noncompetitive inhibition of CYP2C19 (Ki = 140 µM) and CYP3A4 (Ki = 692.86 µM). Results from this study provided the potential information that both asiaticoside and madecassoside are probable to cause drug–drug interactions with medicines that are metabolized by CYP2C19 and CYP3A4. Further investigation is needed to evaluate whether these inhibitory effects of both compounds on both CYP isoforms are clinically significant.