We investigated the involvement of drug transporters in the pharmacokinetics of rosmarinic acid in rats as well as the transporter-mediated drug interaction potential of rosmarinic acid in HEK293 cells overexpressing clinically important solute carrier transporters and also in rats. Intravenously injected rosmarinic acid showed bi-exponential decay and unchanged rosmarinic acid was mainly eliminated by urinary excretion, suggesting the involvement of transporters in its renal excretion. Rosmarinic acid showed organic anion transporter (OAT)1-mediated active transport with a K_m of 26.5 μM and a V_max of 69.0 pmol/min in HEK293 cells overexpressing OAT1, and the plasma concentrations of rosmarinic acid were increased by the co-injection of probenecid because of decreased renal excretion due to OAT1 inhibition. Rosmarinic acid inhibited the transport activities of OAT1, OAT3, organic anion transporting polypeptide (OATP)1B1, and OATP1B3 with IC₅₀ values of 60.6 μM, 1.52 μM, 74.8 μM, and 91.3 μM, respectively, and the inhibitory effect of rosmarinic acid on OAT3 transport activity caused an in vivo pharmacokinetic interaction with furosemide by inhibiting its renal excretion and by increasing its plasma concentration. In conclusion, OAT1 and OAT3 are the major transporters that may regulate the pharmacokinetic properties of rosmarinic acid and may cause herb-drug interactions with rosmarinic acid, although their clinical relevance awaits further evaluation.

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有机阴离子转运蛋白参与迷迭香酸的药代动力学和药物相互作用

我们调查了迷迭香酸在大鼠的药代动力学中药物转运蛋白的参与，以及迷迭香酸在过表达临床上重要的溶质载体转运蛋白的HEK293细胞中以及在大鼠中的转运蛋白介导的药物相互作用潜力。静脉注射迷迭香酸显示双指数衰减，而迷迭香酸不变主要通过尿排泄消除，表明转运蛋白参与了其肾排泄。迷迭香酸显示出有机阴离子转运蛋白（OAT）1介导的主动转运，K _m为26.5μM，V _max在过量表达OAT1的HEK293细胞中，有69.0 pmol / min的血红蛋白，而丙磺舒的共同注射增加了迷迭香酸的血浆浓度，因为OAT1抑制导致肾脏排泄减少。迷迭香酸通过IC ₅₀抑制OAT1，OAT3，有机阴离子转运多肽（OATP）1B1和OATP1B3的转运活性值分别为60.6μM，1.52μM，74.8μM和91.3μM，而迷迭香酸对OAT3转运活性的抑制作用通过抑制呋塞米的肾脏排泄和增加血浆浓度而引起了与呋塞米的体内药代动力学相互作用。总之，OAT1和OAT3是可能调节迷迭香酸药代动力学特性并可能引起草药与迷迭香酸相互作用的主要转运蛋白，尽管它们的临床相关性尚待进一步评估。