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

• Published in: Journal of agricultural and food chemistry 2020-02, Vol.68 (5), p.1257-1265
• Main Authors: Kotwal, Pankul, Dogra, Ashish, Sharma, Ankita, Bhatt, Shipra, Gour, Abhishek, Sharma, Sumit, Wazir, Priya, Singh, Parvinder Pal, Kumar, Ajay, Nandi, Utpal
• Format: Article
• Language: English
• Subjects: Animals; Antitubercular Agents - administration & dosage; Antitubercular Agents - pharmacokinetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Diarylquinolines - administration & dosage; Diarylquinolines - pharmacokinetics; Dietary Supplements - adverse effects; Dietary Supplements - analysis; Female; Food-Drug Interactions; Humans; Phenols - administration & dosage; Phenols - adverse effects; Plant Extracts - administration & dosage; Plant Extracts - adverse effects; Rats; Rats, Wistar; Tuberculosis, Multidrug-Resistant - drug therapy; Tuberculosis, Multidrug-Resistant - genetics; Tuberculosis, Multidrug-Resistant - metabolism
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.9b06529

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.