CEA, DSV, I2BM, Service Hospitalier Frédéric Joliot, Orsay, 91401, France,
AAPS J. 2013 Oct;15(4):1082-90. doi: 10.1208/s12248-013-9514-2. Epub 2013 Aug 2.
Glyburide (glibenclamide, GLB) is a widely prescribed antidiabetic with potential beneficial effects in central nervous system injury and diseases. In vitro studies show that GLB is a substrate of organic anion transporting polypeptide (OATP) and ATP-binding cassette (ABC) transporter families, which may influence GLB distribution and pharmacokinetics in vivo. In the present study, we used [(11)C]GLB positron emission tomography (PET) imaging to non-invasively observe the distribution of GLB at a non-saturating tracer dose in baboons. The role of OATP and P-glycoprotein (P-gp) in [(11)C]GLB whole-body distribution, plasma kinetics, and metabolism was assessed using the OATP inhibitor rifampicin and the dual OATP/P-gp inhibitor cyclosporine. Finally, we used in situ brain perfusion in mice to pinpoint the effect of ABC transporters on GLB transport at the blood-brain barrier (BBB). PET revealed the critical role of OATP on liver [(11)C]GLB uptake and its subsequent impact on [(11)C]GLB metabolism and plasma clearance. OATP-mediated uptake also occurred in the myocardium and kidney parenchyma but not the brain. The inhibition of P-gp in addition to OATP did not further influence [(11)C]GLB tissue and plasma kinetics. At the BBB, the inhibition of both P-gp and breast cancer resistance protein (BCRP) was necessary to demonstrate the role of ABC transporters in limiting GLB brain uptake. This study demonstrates that GLB distribution, metabolism, and elimination are greatly dependent on OATP activity, the first step in GLB hepatic clearance. Conversely, P-gp, BCRP, and probably multidrug resistance protein 4 work in synergy to limit GLB brain uptake.
格列吡嗪（glibenclamide，GLB）是一种广泛应用的抗糖尿病药物，具有潜在的中枢神经系统损伤和疾病的有益作用。体外研究表明，GLB 是有机阴离子转运多肽（OATP）和 ATP 结合盒（ABC）转运体家族的底物，这可能影响 GLB 在体内的分布和药代动力学。在本研究中，我们使用 [(11)C]GLB 正电子发射断层扫描（PET）成像，在非饱和示踪剂量下非侵入性地观察 GLB 在狒狒体内的分布。使用 OATP 抑制剂利福平（rifampicin）和双重 OATP/P-gp 抑制剂环孢菌素（cyclosporine）评估 OATP 和 P-糖蛋白（P-gp）在 [(11)C]GLB 全身分布、血浆动力学和代谢中的作用。最后，我们使用小鼠原位脑灌注来确定 ABC 转运体对 GLB 在血脑屏障（BBB）中的转运的影响。PET 揭示了 OATP 对肝脏 [(11)C]GLB 摄取的关键作用，及其随后对 [(11)C]GLB 代谢和血浆清除的影响。OATP 介导的摄取也发生在心肌和肾脏实质中，但不在大脑中。除 OATP 外，P-gp 的抑制作用不会进一步影响 [(11)C]GLB 组织和血浆动力学。在 BBB 中，P-gp 和乳腺癌耐药蛋白（BCRP）的抑制作用是必要的，以证明 ABC 转运体在限制 GLB 脑摄取中的作用。这项研究表明，GLB 的分布、代谢和消除在很大程度上取决于 OATP 的活性，这是 GLB 肝脏清除的第一步。相反，P-gp、BCRP 以及可能的多药耐药蛋白 4 协同作用以限制 GLB 脑摄取。
