Effect of Natural Phenolics on Pharmacokinetic Modulation of Bedaquiline in Rat to Assess the Likelihood of Potential Food–Drug Interaction

Abstract

Bedaquiline (TMC-207) is a recently approved drug for the treatment of multidrug-resistant tuberculosis (MDR-TB). Moreover, there is a present and growing concern for natural-product-mediated drug interaction, as these are inadvertently taken by patients as a dietary supplement, food additive, and medicine. In the present study, we investigated the impact of 20 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 coadministration. We further investigated the possible role of all of the phytochemicals on in vitro P-glycoprotein (P-gp) induction and inhibition and CYP3A4 inhibition 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 coadministered with bedaquiline to avoid untoward drug interactions and, subsequently, its dose-dependent adverse effects.

Effect of Disease State on the Pharmacokinetics of Bedaquiline in Renal-Impaired and Diabetic Rats

“…The volume of distribution ( V d / F ) and clearance (Cl/ F ) of bedaquiline after oral administration were 26 ± 13 L/kg and 1.7 ± 0.4 L/h/kg, respectively. This is the first time report for oral pharmacokinetics of bedaquiline in any preclinical model where all the important pharmacokinetic parameters are described based on a detailed investigation for 24 h …”

Discovery of Novel 3,4-Dichloroisothiazole-Containing Coumarins as Fungicidal Leads

“…Natural products are the metabolites of animals, microbes, and plants, which have advantages of biocompatibility, structural diversity, target specificity, unique mechanism, and lower resistance risk. − They are one of the resources used for discovering novel drugs and agrochemicals by derivations/modifications, which are usually aimed to improve potency, reduce side effects, manipulate physicochemical parameters, etc. − Coumarins ( 2H -1-benzopyran-2-ones) are a class of important natural products exhibiting impressive pharmacological and physiological activities such as anticoagulant, antibacterial, antiviral, antitumor, bactericidal, fungicidal, anti-inflammatory agents and anti-HIV activity. − Because of their cytotoxicity, few coumarins have been commercialized as agrochemicals. However, coumarins are also considered as plant phytoalexins for defenses against pathogen attacks. , Osthole (Figure ), separated from Cnidium monnieri (a traditional Chinese herbal medicine), has been registered and commercialized as a fungicide against Pseudoperonospora cubensis (Berk.…”

Therapeutic Potential of Curcumin as an Antimycobacterial Agent

“…Twelve grams per day intake of curcumin has no harmful effects on healthy individuals [ 57 , 58 ]. However, in vitro analysis of the effect of curcumin on LS180 cells for P-glycoprotein (P-gp) induction/inhibition and CYP3A4 inhibition in a single platform showed curcumin should not be administered with bedaquiline (TMC-207), a recently approved drug for the treatment of multidrug-resistant tuberculosis (MDRTB), because both bedaquiline and curcumin are substrates for both P-gp and CYP3A4 [ 59 ].…”