Preincubation With Everolimus and Sirolimus Reduces Organic Anion-Transporting Polypeptide (OATP)1B1-and 1B3-Mediated Transport Independently of mTOR Kinase Inhibition: Implication in Assessing OATP1B1-and OATP1B3-Mediated Drug-Drug Interactions
Preincubation With Everolimus and Sirolimus Reduces Organic Anion-Transporting Polypeptide (OATP)1B1-and 1B3-Mediated Transport Independently of mTOR Kinase Inhibition: Implication in Assessing OATP1B1-and OATP1B3-Mediated Drug-Drug Interactions
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DOI：
10.1016/j.xphs.2019.04.019
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发表时间：
2019-10-01
影响因子：
3.8
通讯作者：
Yue, Wei
中科院分区：
文献类型：
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作者：
Farasyn, Taleah;Crowe, Alexandra;Yue, Wei
有机阴离子转运多肽（OATP）1B 1和OATP 1B 3介导许多药物（包括降脂他汀类药物）的肝脏摄取。目前的研究使用R值和基于生理学的药代动力学模型确定了哺乳动物雷帕霉素靶点（mTOR）抑制剂依维莫司和西罗莫司的OATP 1B 1/1B 3介导的药物相互作用（DDI）潜力。与依维莫司和西罗莫司预孵育可显著降低OATP 1B 1/1B 3介导的转运，即使在清洗后也是如此，OATP 1B 1的抑制常数值分别降低至8.3倍和2.9倍，OATP 1B 3的抑制常数值均降低至2.7倍。依维莫司的R值大于FDA推荐的临界值1.1，而西罗莫司则不然。基于生理学的药代动力学模型预测，依维莫司和西罗莫司对普伐他汀的OATP 1B 1/1B 3介导DDI潜力较低。OATP 1B 1/1B 3介导的转运不受INK-128预孵育（10 μ M，1 h）的影响，但可消除mTOR激酶活性。在与溶剂对照或INK-128预孵育前，依维莫司和西罗莫司对OATP 1B 1/1B 3介导转运的预孵育作用在细胞中相似，表明mTOR活性抑制不是观察到的依维莫司和西罗莫司预孵育作用的先决条件。通过磷酸化蛋白质组学鉴定了OATP 1B 1的9个潜在磷酸化位点;这些位点均不是预测的mTOR磷酸化位点。我们报告了依维莫司/西罗莫司预孵育诱导的对OATP 1B 1/1B 3的抑制作用，以及依维莫司和西罗莫司相对较低的OATP 1B 1/1B 3介导的DDI潜力。(c)2019年美国药学协会（R）。爱思唯尔公司出版All rights reserved.
Organic anion transporting polypeptides (OATP)1B1 and OATP1B3 mediate hepatic uptake of many drugs including lipid-lowering statins. Current studies determined the OATP1B1/1B3-mediated drug-drug interaction (DDI) potential of mammalian target of rapamycin (mTOR) inhibitors, everolimus and sirolimus, using R-value and physiologically based pharmacokinetic models. Preincubation with everolimus and sirolimus significantly decreased OATP1B1/1B3-mediated transport even after washing and decreased inhibition constant values up to 8.3- and 2.9-fold for OATP1B1 and both 2.7-fold for OATP1B3, respectively. R-values of everolimus, but not sirolimus, were greater than the FDA-recommended cutoff value of 1.1. Physiologically based pharmacokinetic models predict that everolimus and sirolimus have low OATP1B1/1B3-mediated DDI potential against pravastatin. OATP1B1/1B3-mediated transport was not affected by preincubation with INK-128 (10 mu M, 1 h), which does however abolish mTOR kinase activity. The preincubation effects of everolimus and sirolimus on OATP1B1/1B3-mediated transport were similar in cells before preincubation with vehicle control or INK-128, suggesting that inhibition of mTOR activity is not a prerequisite for the preincubation effects observed for everolimus and sirolimus. Nine potential phosphorylation sites of OATP1B1 were identified by phosphoproteomics; none of these are the predicted mTOR phosphorylation sites. We report the everolimus/sirolimus-preincubation-induced inhibitory effects on OATP1B1/1B3 and relatively low OATP1B1/1B3-mediated DDI potential of everolimus and sirolimus. (c) 2019 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.