Potential Interaction of Pinocembrin with Drug Transporters and Hepatic Drug-Metabolizing Enzymes

  • Pharmaceuticals (Basel). 2025 Jan 1;18(1):42. doi: 10.3390/ph18010042.
Sirima Sangkapat  1 ,  Rattiporn Boonnop  2 ,  Jeerawat Pimta  2 ,  Napason Chabang  3 ,  Bodee Nutho  4 ,  Promsuk Jutabha  5 ,  Sunhapas Soodvilai  2  6
Affiliations
  • 1. Department of Pharmaceutical Technology, College of Pharmacy, Rangsit University, Pathumthani 12000, Thailand.
  • 2. Research Center of Transport Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, Thailand.
  • 3. School of Bioinnovation and Bio-based Product Intelligence (SCIN), Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, Thailand.
  • 4. Department of Pharmacology, Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, Thailand.
  • 5. Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli, Samut Prakan 10540, Thailand.
  • 6. Excellent Center for Drug Discovery, Mahidol University, Ratchathewi, Bangkok 10400, Thailand.
PMID: 39861105 DOI: 10.3390/ph18010042
Abstract

Background/Objectives: Pinocembrin is a promising drug candidate for treating ischemic stroke. The interaction of pinocembrin with drug transporters and drug-metabolizing Enzymes is not fully revealed. The present study aims to evaluate the interaction potential of pinocembrin with Cytochrome P450 (CYP450: CYP2B6, CYP2C9, and CYP2C19) and drug transporters including organic anion transporters (OAT1 and OAT3), organic cation transporters (OCT1 and OCT2), multidrug and toxin extrusion (MATE1 and MATE2, P-glycoprotein (P-gp), and breast Cancer resistance protein (BCRP). Methods: The interactions of pinocembrin on drug transporters were determined in the Madin-Darby canine kidney (MDCK) cells overexpressing human (h)OAT1 or hOAT3 and in the Chinese hamster ovary (CHO-K1) cells overexpressing hOCT1, hOCT2, hMATE1, or hMATE2. The interactions of pinocembrin with BCRP and P-glycoprotein were determined in Caco-2 cells. The CYP450 enzyme inhibitory activity was assessed by a cell-free CYP450 screening assay. Results: Pinocembrin effectively inhibited the function of OAT1 and OAT3 with a half-inhibitory concentration (IC50) and inhibitory constant (Ki) of ∼2 μM. In addition, it attenuated the toxicity of tenofovir, a substrate of hOAT1, in cells overexpressing hOAT1. Based on the kinetic study and molecular docking, pinocembrin inhibited OAT1 and OAT3 via a competitive inhibition. In contrast to hOAT1 and hOAT3, pinocembrin did not significantly inhibit the function of OCT1, OCT2, MATE1, MATE2, BCRP, and P-glycoprotein. In addition, pinocembrin potently inhibited the activity of CYP2C19, whereas it exhibited low inhibitory potency on CYP2B6 and CYP2C9. Conclusions: The present study reveals the potential drug interaction of pinocembrin on OAT1, OAT3, and CYP2C19. Co-administration with pinocembrin might affect OAT1-, OAT3-, and CYP2C19-mediated drug pharmacokinetic profiles.

Keywords
CYP2C19; OAT1; OAT3; drug development; drug interaction; flavonoids.
Products
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    Description
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    Ko 143
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