RT Journal Article SR Electronic T1 Centella asiatica water extract shows low potential for CYP-mediated drug interactions JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.120.090860 DO 10.1124/dmd.120.090860 A1 Kirsten M. Wright A1 Armando Alcazar Magaña A1 Ronald M. Laethem A1 Caroline L. Moseley A1 Troy T. Banks A1 Claudia S. Maier A1 Jan F. Stevens A1 Joseph F. Quinn A1 Amala Soumyanath YR 2020 UL http://dmd.aspetjournals.org/content/early/2020/06/24/dmd.120.090860.abstract AB Centella asiatica (CA) shows considerable promise for development as a botanical drug for cognitive decline. Its primary bioactive components include triterpene glycosides asiaticoside and madecassoside, and their corresponding aglycones asiatic acid and madecassic acid. Exploration of CA's caffeoylquinic acids' bioactivity is ongoing. In this study, an aqueous extract of CA (CAW-R61J) was evaluated for drug interaction potential through inhibition or induction of CYP enzymes, as required by the US Food and Drug Administration. CAW-R61J was assessed for induction potential of CYP1A2, CYP2B6, and CYP3A4 using transporter certified cryopreserved human hepatocytes in sandwich culture. Gene expression of these target CYPs was quantified, and enzyme activities determined to confirm gene expression results. No induction was observed up to 16.7 µg/mL CAW-R61J (equivalent to 1.1 µM asiaticoside 0.8 µM madecassoside, 0.09 µM asiatic acid and 0.12 µM madecassic acid). Reversible and time-dependent inhibitory effects of CAW-R61J on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 were evaluated using human liver microsomes. CAW-R61J showed weak reversible inhibiton of most of the CYP forms tested; the strongest being of CYP2C9 (IC50 of 330 µg/mL). CAW-R61J (≤ 1000 µg/mL) was not a time-dependent inhibitor of any of these CYP enzymes. In summary, CAW-R61J had no, or only a weak impact on CYP induction and inhibition in vitro. The clinical relevance of these results will depend on the in vivo concentration of CAW-R61J components achieved in humans. Plasma triterpene concentrations measured in our recent clinical studies suggest minimal risk of CYP-mediated drug interactions by these components.SIGNIFICANCE STATEMENT A preparation of Centella asiatica is currently under clinical development for the prevention or treatment of cognitive decline. The US Food and Drug administration required an evaluation of its potential for drug interactions mediated through drug metabolizing enzymes. This in vitro study revealed minimal induction or inhibition of a range of CYP enzymes including CYP3A4 by the Centella asiatica extract, suggesting a low potential for drug interactions modulated by CYP metabolism.