Eli Lilly and Company, Indianapolis, Indiana, USA.
Current address: Organovo Inc., San Diego, California, USA.
Clin Transl Sci. 2017 Nov;10(6):509-519. doi: 10.1111/cts.12486. Epub 2017 Jul 27.
Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, undergoes active renal tubular secretion. Baricitinib was not predicted to inhibit hepatic and renal uptake and efflux drug transporters, based on the ratio of the unbound maximum eliminating-organ inlet concentration and the in vitro half-maximal inhibitory concentrations (IC ). In vitro, baricitinib was a substrate for organic anion transporter (OAT)3, multidrug and toxin extrusion protein (MATE)2-K, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Probenecid, a strong OAT3 inhibitor, increased the area under the concentration-time curve from time zero to infinity (AUC ) of baricitinib by twofold and decreased renal clearance to 69% of control in healthy subjects. Physiologically based pharmacokinetic (PBPK) modeling reproduced the renal clearance of baricitinib and the inhibitory effect of probenecid using the in vitro IC value of 4.4 μM. Using ibuprofen and diclofenac in vitro IC values of 4.4 and 3.8 μM toward OAT3, 1.2 and 1.0 AUC ratios of baricitinib were predicted. These predictions suggest clinically relevant drug-drug interactions (DDIs) with ibuprofen and diclofenac are unlikely.
巴利昔替尼是一种口服选择性 Janus 激酶 1 和 2 抑制剂，经主动肾小管分泌。根据未结合最大消除器官入口浓度与体外半最大抑制浓度 (IC ) 的比值，巴利昔替尼不太可能抑制肝摄取和肾摄取及外排药物转运体。体外研究表明，巴利昔替尼是有机阴离子转运蛋白 (OAT)3、多药和毒素外排蛋白 (MATE)2-K、P-糖蛋白 (P-gp) 和乳腺癌耐药蛋白 (BCRP) 的底物。丙磺舒是一种强效 OAT3 抑制剂，使健康受试者的巴利昔替尼 AUC 增加了一倍，从零到无穷大 (AUC )，并使肾清除率降低至对照的 69%。基于生理学的药代动力学 (PBPK) 模型使用 4.4 μM 的体外 IC 值再现了巴利昔替尼的肾清除率和丙磺舒的抑制作用。体外研究表明，OAT3 的 IC 值分别为 4.4 和 3.8 μM 的布洛芬和双氯芬酸，预测巴利昔替尼的 AUC 比值分别为 1.2 和 1.0。这些预测表明，巴利昔替尼与布洛芬和双氯芬酸之间不太可能发生具有临床意义的药物相互作用 (DDI)。
