Potential Interaction of Pinocembrin with Drug Transporters and Hepatic Drug-Metabolizing Enzymes
<b>Background/Objectives</b>: 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 wit...
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2025-01-01
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| author | Sirima Sangkapat Rattiporn Boonnop Jeerawat Pimta Napason Chabang Bodee Nutho Promsuk Jutabha Sunhapas Soodvilai |
| author_facet | Sirima Sangkapat Rattiporn Boonnop Jeerawat Pimta Napason Chabang Bodee Nutho Promsuk Jutabha Sunhapas Soodvilai |
| author_sort | Sirima Sangkapat |
| collection | DOAJ |
| description | <b>Background/Objectives</b>: 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). <b>Methods</b>: 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. <b>Results</b>: Pinocembrin effectively inhibited the function of OAT1 and OAT3 with a half-inhibitory concentration (IC<sub>50</sub>) 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. <b>Conclusions</b>: 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. |
| format | Article |
| id | doaj-art-e7763101e9e24545af1dd2b85acfa3a3 |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-e7763101e9e24545af1dd2b85acfa3a32025-01-24T13:45:08ZengMDPI AGPharmaceuticals1424-82472025-01-011814210.3390/ph18010042Potential Interaction of Pinocembrin with Drug Transporters and Hepatic Drug-Metabolizing EnzymesSirima Sangkapat0Rattiporn Boonnop1Jeerawat Pimta2Napason Chabang3Bodee Nutho4Promsuk Jutabha5Sunhapas Soodvilai6Department of Pharmaceutical Technology, College of Pharmacy, Rangsit University, Pathumthani 12000, ThailandResearch Center of Transport Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, ThailandResearch Center of Transport Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, ThailandSchool of Bioinnovation and Bio-based Product Intelligence (SCIN), Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, ThailandDepartment of Pharmacology, Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, ThailandChakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli, Samut Prakan 10540, ThailandResearch Center of Transport Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, Thailand<b>Background/Objectives</b>: 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). <b>Methods</b>: 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. <b>Results</b>: Pinocembrin effectively inhibited the function of OAT1 and OAT3 with a half-inhibitory concentration (IC<sub>50</sub>) 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. <b>Conclusions</b>: 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.https://www.mdpi.com/1424-8247/18/1/42OAT1OAT3CYP2C19flavonoidsdrug interactiondrug development |
| spellingShingle | Sirima Sangkapat Rattiporn Boonnop Jeerawat Pimta Napason Chabang Bodee Nutho Promsuk Jutabha Sunhapas Soodvilai Potential Interaction of Pinocembrin with Drug Transporters and Hepatic Drug-Metabolizing Enzymes Pharmaceuticals OAT1 OAT3 CYP2C19 flavonoids drug interaction drug development |
| title | Potential Interaction of Pinocembrin with Drug Transporters and Hepatic Drug-Metabolizing Enzymes |
| title_full | Potential Interaction of Pinocembrin with Drug Transporters and Hepatic Drug-Metabolizing Enzymes |
| title_fullStr | Potential Interaction of Pinocembrin with Drug Transporters and Hepatic Drug-Metabolizing Enzymes |
| title_full_unstemmed | Potential Interaction of Pinocembrin with Drug Transporters and Hepatic Drug-Metabolizing Enzymes |
| title_short | Potential Interaction of Pinocembrin with Drug Transporters and Hepatic Drug-Metabolizing Enzymes |
| title_sort | potential interaction of pinocembrin with drug transporters and hepatic drug metabolizing enzymes |
| topic | OAT1 OAT3 CYP2C19 flavonoids drug interaction drug development |
| url | https://www.mdpi.com/1424-8247/18/1/42 |
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