Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York.
Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
Clin Cancer Res. 2021 Aug 1;27(15):4301-4310. doi: 10.1158/1078-0432.CCR-21-0023. Epub 2021 Mar 4.
OATP1B1 (SLCO1B1) is the most abundant and pharmacologically relevant uptake transporter in the liver and a key mediator of xenobiotic clearance. However, the regulatory mechanisms that determine OATP1B1 activity remain uncertain, and as a result, unexpected drug-drug interactions involving OATP1B1 substrates continue to be reported, including several involving tyrosine kinase inhibitors (TKI).
OATP1B1-mediated activity in overexpressing HEK293 cells and hepatocytes was assessed in the presence of FDA-approved TKIs, while rosuvastatin pharmacokinetics in the presence of an OATP1B1 inhibiting TKI were measured . Tyrosine phosphorylation of OATP1B1 was determined by LC/MS-MS-based proteomics and transport function was measured following exposure to siRNAs targeting 779 different kinases.
Twenty-nine of 46 FDA-approved TKIs studied significantly inhibit OATP1B1 function. Inhibition of OATP1B1 by TKIs, such as nilotinib, is predominantly noncompetitive, can increase systemic concentrations of rosuvastatin , and is associated with reduced phosphorylation of OATP1B1 at tyrosine residue 645. Using genetic screens and functional validation studies, the Src kinase LYN was identified as a potential regulator of OATP1B1 activity that is highly sensitive to inhibition by various TKIs at clinically relevant concentrations.
A novel kinase-dependent posttranslational mechanism of OATP1B1 activation was identified and interference with this process by TKIs can influence the elimination of a broad range of xenobiotic substrates.
OATP1B1（SLCO1B1）是肝脏中最丰富和最具药理学相关性的摄取转运体，也是外源性物质清除的关键介质。然而，决定 OATP1B1 活性的调节机制仍不确定，因此，涉及 OATP1B1 底物的意外药物相互作用仍在不断被报道，包括几种涉及酪氨酸激酶抑制剂（TKI）的药物相互作用。
在存在 FDA 批准的 TKI 的情况下，评估 OATP1B1 在过表达 HEK293 细胞和肝细胞中的介导活性，同时测量存在 OATP1B1 抑制性 TKI 时的罗苏伐他汀药代动力学。通过基于 LC/MS-MS 的蛋白质组学测定 OATP1B1 的酪氨酸磷酸化，并用靶向 779 种不同激酶的 siRNA 暴露后测量转运功能。
在所研究的 46 种 FDA 批准的 TKI 中，有 29 种明显抑制 OATP1B1 功能。TKI 如 nilotinib 对 OATP1B1 的抑制主要是非竞争性的，可增加 rosuvastatin 的系统浓度，并与 OATP1B1 酪氨酸残基 645 的磷酸化减少相关。通过遗传筛选和功能验证研究，鉴定出Src 激酶 LYN 是 OATP1B1 活性的潜在调节因子，它对各种 TKI 在临床相关浓度下的抑制非常敏感。
确定了 OATP1B1 激活的新型激酶依赖性翻译后机制，TKI 对该过程的干扰会影响广泛外源性底物的消除。
