Evaluation of possible pharmacokinetic interaction between methotrexate and proton pump inhibitors in rats
Evaluation of possible pharmacokinetic interaction between methotrexate and proton pump inhibitors in rats
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DOI：
10.1007/s43440-020-00130-1
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发表时间：
2020-07
影响因子：
4.4
通讯作者：
Hinata Ueda;Katsuya Narumi;Yuki Sato;Ayako Furugen;Masaki Kobayashi;K. Iseki
中科院分区：
文献类型：
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作者：
Hinata Ueda;Katsuya Narumi;Yuki Sato;Ayako Furugen;Masaki Kobayashi;K. Iseki
背景甲氨蝶呤 (MTX) 是一种抗叶酸剂，主要通过肾脏消除。有机阴离子转运蛋白 3 (OAT3) 有助于肾脏 MTX 清除。多项研究表明，同时服用质子泵抑制剂 (PPI) 与 MTX 延迟消除之间存在关联，但研究结果相互矛盾。在本研究中，我们旨在评估 PPI 对 OAT3 介导的 MTX 转运的差异抑制作用是否与延迟 MTX 消除的风险相关。方法我们使用表达 rOAT3 的 HEK293T 细胞研究了 PPI 对大鼠 (r) OAT3 介导的 MTX 摄取的影响。为了检查 PPI 是否会影响 MTX 的药代动力学，对大鼠给予 MTX（50 mg/kg，腹腔注射）和一系列 PPI（2 mg/kg，静脉注射）时血浆浓度-时间曲线的变化进行了评估。结果体外研究表明，PPI 抑制 rOAT3 介导的 MTX 摄取，估计 IC50 值为 2.1–5.2 μM，埃索美拉唑 ≈ 兰索拉唑 ≈ 奥美拉唑 > 雷贝拉唑。当MTX和埃索美拉唑共同给予大鼠时，给药后6小时的MTX血浆浓度和t1/2均显着高于媒介物组。兰索拉唑的作用并不显着，但表现出延长血浆MTX水平的趋势。组胺 H2 受体拮抗剂法莫替丁对 rOAT3 介导的 MTX 摄取表现出较弱的抑制作用，但不影响体内 MTX 的血浆浓度-时间曲线。 结论埃索美拉唑增加大鼠 MTX 的 t1/2，部分原因可能是抑制 rOAT3。
BackgroundMethotrexate (MTX), an antifolate agent, is primarily eliminated by the kidney. Organic anion transporter 3 (OAT3) contributes to renal MTX clearance. Several studies have shown an association between co-administration of proton pump inhibitors (PPIs) and delayed elimination of MTX, but the findings are conflicting. In this study, we aimed to evaluate whether the differential inhibitory effects of PPIs on the OAT3-mediated transport of MTX are associated with the risks of delayed MTX elimination.MethodsWe investigated the effects of PPIs on rat (r) OAT3-mediated MTX uptake using HEK293T cells expressing rOAT3. To examine whether PPIs could affect the pharmacokinetics of MTX, changes in plasma concentration–time profiles were assessed when MTX (50 mg/kg, ip) and a range of PPIs (2 mg/kg, iv) were administered to rats.ResultsIn vitro studies demonstrated that PPIs inhibited rOAT3-mediated uptake of MTX, with estimated IC50values of 2.1–5.2 μM, and a rank order of esomeprazole ≈ lansoprazole ≈ omeprazole > rabeprazole. When MTX and esomeprazole were co-administered to rats, the plasma concentration of MTX 6 h after administration and thet1/2were significantly higher than those in the vehicle group. The effect of lansoprazole was not significant, but showed a tendency to prolong plasma MTX levels. Famotidine, a histamine H2-receptor antagonist, showed a weak inhibitory effect on rOAT3-mediated MTX uptake, although it did not affect plasma concentration–time profile of MTX in vivo.ConclusionEsomeprazole increases thet1/2of MTX in rats, which may be partially attributed to the inhibition of rOAT3.