Abstract
BACKGROUND: Herbal drugs are often used alongside conventional cancer therapies to mitigate the adverse effects and enhance therapeutic efficacy. Triphala, a traditional herbal formulation used in Ayurveda, is known for its anticancer and CYP2E1 inhibitory properties. Cisplatin, although highly effective in cancer treatment, is known to cause significant hepatotoxicity and nephrotoxicity which are mediated by toxic metabolites formed through CYP2E1 metabolism. OBJECTIVE: The objective of this study is to explore the pharmacokinetic drug interactions between Triphala and cisplatin. METHODS: At the outset, the pharmacokinetic interactions between Triphala and cisplatin were confirmed by in-vitro experiments using HepG2 and 786-0 cell lines based on Reactive Oxygen Species (ROS) generation and cell viability assay, and in-vivo study using Sprague Dawley rats based on serum cisplatin concentration. Later, the literature derived phytoconstituents were subjected to in-silico studies to investigate their molecular interactions with the metabolizing enzyme CYP2E1. RESULTS: In-vitro studies revealed a reduction in ROS generation and enhanced cell viability, indicating that the metabolism of cisplatin is hindered by Triphala, which was attributed to its CYP2E1 inhibitory potential. In-vivo studies showed a marginal increase in cisplatin concentrations in rat serum that received the combination of Triphala and cisplatin, supporting the in-vitro findings. In-silico studies revealed that Triphala constituents, especially gallic acid and 3,5-dihydroxy-4-methoxybenzoic acid, stably bind and potentially inhibit CYP2E1 via key interactions with THR303. CONCLUSION: The results suggest that Triphala may interact with cisplatin by inhibiting the CYP2E1 enzyme, potentially affecting the metabolism and toxicity of cisplatin. These findings highlight the need for further research to evaluate the clinical implications of using Triphala alongside cisplatin-based cancer therapies.