Effect of natural phenolics on pharmacokinetic modulation of bedaquiline in rat to assess the likelihood of potential food-drug interaction

Bedaquiline (TMC-207) is a recently approved drug for the treatment of multi-drug-resistant tuberculosis. Moreover, there is a present and growing concern for natural product-mediated drug interaction, as these are inadvertently taken by patients as dietary supplement/food additive/medicine as well. In the present study, we investigated the impact of twenty plant-based natural products, typically phenolics, on in-vivo oral bedaquiline pharmacokinetics, as previous studies are lacking. Three natural phenolics were identified that can significantly enhance the oral exposure of bedaquiline upon co-administration. We further investigated the possible role of all the phytochemicals on in-vitro P-gp (induction & inhibition) and CYP3A4 in a single platform as bedaquiline is the substrate for both P-gp and CYP3A4. In conclusion, curcumin, CC-I (3′,5–dihydroxyflavone-7–O–β–D–galacturonide-4′-O–β–D-glucopyranoside) and 6-gingerol should not be co-administered with bedaquiline to avoid untoward drug interactions and...