Centella asiaticaWater Extract Shows Low Potential for Cytochrome P450–Mediated Drug Interactions

Abstract

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 the bioactivity of CA's caffeoylquinic acids is ongoing. In this study, an aqueous extract of CA (CAW-R61J) was evaluated for drug interaction potential through inhibition or induction of P450 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 P450s was quantified, and enzyme activities were determined to confirm gene expression results. No induction was observed up to 16.7 mg/ml CAW-R61J (equivalent to 1.1 mM asiaticoside, 0.8 mM madecassoside, 0.09 mM asiatic acid, and 0.12 mM 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 inhibition of most of the P450 forms tested, with the strongest being CYP2C9 (IC 50 of 330 mg/ml). CAW-R61J (£1000 mg/ml) was not a time-dependent inhibitor of any of these P450 enzymes. In summary, CAW-R61J had no, or only a weak impact, on P450 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 P450-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 P450 enzymes, including CYP3A4, by the C. asiatica extract, suggesting a low potential for drug interactions modulated by P450 metabolism.

Can Asiatic Acid from Centella asiatica Be a Potential Remedy in Cancer Therapy?—A Review

“…These women were clinically diagnosed with granulomatous hepatitis, and the symptoms improved after drug discontinuation [56]. Importantly, C. asiatica extract and AA inhibit the activity of CYP2C9, CYP2D6, and CYP3A4, which suggests a potential risk of drug interactions [57,58]. There is a lack of clinical data on the toxicity and safety of AA alone in the literature, which is a challenge for future researchers.…”

Developing a Rational, Optimized Product of Centella asiatica for Examination in Clinical Trials: Real World Challenges

“…However, the relevance of this evidence to CAW was complicated by the large variability in the type of CA preparations that are used in dietary supplements, as well as in those used in earlier preclinical and clinical studies (19). For example, although previous studies had examined the effects of CA extracts on CYP drug metabolizing enzymes (63)(64)(65)(66)(67), the FDA recommended that we examine and report the drug interaction potential of our CAW water extract specifically (68). Also, since earlier preclinical studies on organ toxicity had been performed using other types of CA extracts (69-72), we obtained organ toxicity data from mice treated with CAW that could be used in the IND application.…”

Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions

“…A well characterized water extract of Centella asiatica, specifically CAW-R61J, is currently undergoing clinical development as a botanical drug to treat cognitive decline (Wright et al, 2020), a common affliction among the elderly population. As part of their Investigational New Drug (IND) application for CAW-R61J, Wright et al (2020) characterized the P450 inhibition properties of this promising natural product using HLMs and standard procedures. CAW-R61J was a weak reversible inhibitor and was not a time-dependent inhibitor of the P450s tested (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A), suggesting low risk for CAW-R61J-precipitated pharmacokinetic drug interactions via P450 inhibition.…”

“…gov/regulatory-information/search-fda-guidance-documents/vitro-druginteraction-studies-cytochrome-p450-enzyme-and-transporter-mediateddrug-interactions). In addition to characterizing the P450 inhibitory effects of CAW-R61J described earlier, Wright et al (2020) assessed the P450 inductive effects of this natural product. Using cryopreserved Canada Natural health products Defined by Health Canada as vitamins and minerals, herbal remedies, homeopathic medicines, traditional medicines such as traditional Chinese medicines, probiotics, and other products such as amino acids and essential fatty acids.…”