Sangkapat Sirima, Boonnop Rattiporn, Pimta Jeerawat, Chabang Napason, Nutho Bodee, Jutabha Promsuk, Soodvilai Sunhapas
Department of Pharmaceutical Technology, College of Pharmacy, Rangsit University, Pathumthani 12000, Thailand.
Research Center of Transport Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, Thailand.
Pharmaceuticals (Basel). 2025 Jan 1;18(1):42. doi: 10.3390/ph18010042.
: 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). : 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. : Pinocembrin effectively inhibited the function of OAT1 and OAT3 with a half-inhibitory concentration (IC) 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. : 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.
白杨素是一种有前景的治疗缺血性中风的候选药物。白杨素与药物转运体和药物代谢酶之间的相互作用尚未完全明确。本研究旨在评估白杨素与细胞色素P450（CYP450：CYP2B6、CYP2C9和CYP2C19）以及药物转运体（包括有机阴离子转运体（OAT1和OAT3）、有机阳离子转运体（OCT1和OCT2）、多药和毒素外排转运体（MATE1和MATE2）、P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP））之间的相互作用潜力。：在过表达人（h）OAT1或hOAT3的Madin-Darby犬肾（MDCK）细胞以及过表达hOCT1、hOCT2、hMATE1或hMATE2的中国仓鼠卵巢（CHO-K1）细胞中测定白杨素对药物转运体的相互作用。在Caco-2细胞中测定白杨素与BCRP和P-糖蛋白的相互作用。通过无细胞CYP450筛选试验评估CYP450酶抑制活性。：白杨素以约2μM的半抑制浓度（IC）和抑制常数（Ki）有效抑制OAT1和OAT3的功能。此外，它减弱了hOAT1底物替诺福韦在过表达hOAT1的细胞中的毒性。基于动力学研究和分子对接，白杨素通过竞争性抑制作用抑制OAT1和OAT3。与hOAT1和hOAT3不同，白杨素对OCT1、OCT2、MATE1、MATE2、BCRP和P-糖蛋白的功能没有显著抑制作用。此外，白杨素强烈抑制CYP2C19的活性，而对CYP2B6和CYP2C9的抑制作用较弱。：本研究揭示了白杨素对OAT1、OAT3和CYP2C19的潜在药物相互作用。与白杨素联合给药可能会影响OAT1、OAT3和CYP2C19介导的药物药代动力学特征。
