Abstract
The formula of a standardized extract of Centella asiatica (ECa 233) was modified to improve its dissolution, with implications for pharmacokinetics and metabolomic profile. This study aimed to understand the resultant changes in disposition kinetics of ECa 233 and alterations to human metabolome after oral administration. This study was a two-sequence of dosages (250 and 500 mg), with an open-label phase I clinical trial. The modified formula was administered in single and multiple doses to twelve healthy Thai volunteers. The major parent compounds, madecassoside and asiaticoside, were rarely absorbed, instead undergoing biotransformation into active metabolites, madecassic acid and asiatic acid with possibility to be eliminated via fecal route. Increasing the dose of ECa 233 resulted in significantly greater plasma levels of those active metabolites, with accumulation of asiatic acid after multiple oral administration for seven days. Examining the impacts of accumulation behavior on metabolomics, the study traced changes in levels pre- and post-dose of five relevant human metabolites. Administration of ECa 233 was found to be significantly associated with an increase of choline, an endogenous metabolite with documented benefits for learning and memory. Therefore, ECa 233 may be useful in mitigating cognitive impairment, through its role in modulating human metabolites.
Highlights
The formula of a standardized extract of Centella asiatica (ECa 233) was modified to improve its dissolution, with implications for pharmacokinetics and metabolomic profile
Abbreviations AChE Acetylcholinesterase AChEI Acetylcholinesterase inhibitor or cholinesterase inhibitor AEs Adverse events ASS into aglycone (ASA) Asiatic acid ASS Asiaticoside AUC Area under plasma concentration–time curve BMI Body mass index Cl/F Apparent total clearance of the test substance removed from plasma after oral administration Cmax Maximum plasma concentration CPMG Carr-Purcell-Meiboom-Gill pulse ECa 233 Standardized extract of Centella asiatica ESI Electrospray ionization F Absolute oral bioavailability
Focusing on the metabolites at post-dose ( T1h, day 7), these results showed that relative plasma concentrations of L-homoserine significantly decreased while levels of citrulline, O-succinyl-L-homoserine, homocarnosine, and choline were significantly increased after receiving modified formula ECa 233 in comparison to pre-dose levels at T 0
Summary
The formula of a standardized extract of Centella asiatica (ECa 233) was modified to improve its dissolution, with implications for pharmacokinetics and metabolomic profile. This study aimed to understand the resultant changes in disposition kinetics of ECa 233 and alterations to human metabolome after oral administration. Increasing the dose of ECa 233 resulted in significantly greater plasma levels of those active metabolites, with accumulation of asiatic acid after multiple oral administration for seven days. Abbreviations AChE Acetylcholinesterase AChEI Acetylcholinesterase inhibitor or cholinesterase inhibitor AEs Adverse events ASA Asiatic acid ASS Asiaticoside AUC Area under plasma concentration–time curve BMI Body mass index Cl/F Apparent total clearance of the test substance removed from plasma after oral administration Cmax Maximum plasma concentration CPMG Carr-Purcell-Meiboom-Gill pulse ECa 233 Standardized extract of Centella asiatica ESI Electrospray ionization F Absolute oral bioavailability. Understanding the associations between changes in the levels of candidate endogenous metabolites and the metabolite-related biomarkers of neurodegenerative d isease[9] is the way to support the step in the use of ECa 233 in clinical practice
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