Abstract

1. Organic anion-transporting polypeptide (OATP) 2B1 plays a critical role in the intestinal absorption of substrate drugs. Apple juice reportedly interacts with OATP2B1 substrate drugs. The purpose of this study was to investigate the effect of two apple polyphenols, phloretin and phloridzin, on OATP2B1-mediated substrate transport in vitro and to evaluate the effect of phloretin on rosuvastatin pharmacokinetics in rats.

2. In vitro studies revealed that both polyphenols inhibited OATP2B1-mediated uptake of estrone-3-sulfate. Despite preincubation with phloretin and subsequent washing, the inhibitory effect was retained. Phloretin markedly decreased OATP2B1-mediated rosuvastatin uptake, with an IC₅₀ value of 3.6 μM.

3. On coadministering rosuvastatin and phloretin in rats, the plasma concentration of rosuvastatin 10 min after oral administration was significantly lower than that in the vehicle group. The area under the plasma concentration-time curve of rosuvastatin was not significant, showing a tendency to decrease in the phloretin group when compared with the vehicle group. The in-situ rat intestinal loop study revealed the inhibitory effect of phloretin on rosuvastatin absorption.

4. Phloretin has potent and long-lasting inhibitory effects on OATP2B1 in vitro. Phloretin may inhibit OATP2B1-mediated intestinal absorption of rosuvastatin; however, it failed to significantly impact the systemic exposure of rosuvastatin in rats.

摘要

1. 有机阴离子转运多肽 (OATP) 2B1 在底物药物的肠道吸收中起关键作用。据报道，苹果汁与 OATP2B1 底物药物相互作用。本研究的目的是研究两种苹果多酚，根皮素和根皮苷，在体外对 OATP2B1 介导的底物转运的影响，并评估根皮素对大鼠瑞舒伐他汀药代动力学的影响。

2. 体外研究表明，这两种多酚都能抑制 OATP2B1 介导的 3-硫酸雌酮摄取。尽管用根皮素预培养并随后洗涤，但仍保留了抑制作用。根皮素显着降低 OATP2B1 介导的瑞舒伐他汀摄取，IC ₅₀值为 3.6 μM。

3. 大鼠同时服用瑞舒伐他汀和根皮素，口服后10分钟瑞舒伐他汀的血浆浓度显着低于赋形剂组。瑞舒伐他汀的血浆浓度-时间曲线下面积不显着，与载体组相比，根皮素组有减少的趋势。在原位大鼠肠袢研究发现的根皮素对瑞舒伐他汀吸收的抑制作用。

4. 根皮素在体外对 OATP2B1 具有强效和持久的抑制作用。根皮素可能抑制 OATP2B1 介导的瑞舒伐他汀的肠道吸收；然而，它未能显着影响大鼠瑞舒伐他汀的全身暴露。