Pharmacokinetic and metabolomic studies of standardized extract of centella asiatica (ECa 233) capsule in Thai healthy volunteers

Abstract

A well-characterized standardized extract of Centella asiatica (ECa 233) being developed as a phytopharmaceutical product for human use was explored in this clinical study. The first objective of this research was to understand changes in disposition kinetics after oral administration of both the original-formula capsule and a newly-modified enhanced-dissolution capsule of ECa 233. Secondly, this study aimed to investigate alteration of human metabolomes following administration of the modified capsule of ECa 233, using an NMR-based metabolomics approach. For pharmacokinetics, the study involved a phase I clinical trial in twelve healthy Thai volunteers, who each received 250 and 500 mg of the original ECa 233 capsule and of the modified ECa 233 capsule, first as a single dose and then a week later as once-daily doses for 7 consecutive days. The results demonstrated that two major parent compounds, madecassoside (MDS) and asiaticoside (ASS), were rarely absorbed but rather underwent extensive biotransformation with minimal renal excretion. Those unabsorbed parent compounds were substituted with two mainly-active metabolites, madecassic acid (MDA) and asiatic acid (ASA). These metabolites were likely excreted through hepatobiliary system by feces elimination. Interestingly, increasing the dose of ECa 233 resulted in significantly greater plasma levels of these active metabolites, with accumulation of asiatic acid after multiple oral administration. Considering metabolomics, this accumulation behavior could affect human metabolome, partly through an alteration between pre- and post-dose of endogenous metabolites detected in plasma. The changes in five relevant metabolites were thoroughly considered to identify candidate biomarkers; these were L-homoserine, citrulline, O-succinyl L-homoserine, homocarnosine, and choline. In particular, ECa 233 was associated with a significant increase in levels of choline, an endogenous metabolite reported to have benefits for learning and memory. This finding suggests that ECa 233 may adjust human metabolic profiles and in this way play a role in fulfilling endogenous metabolites, which might be useful in mitigating cognitive impairment in phase II clinical study.