Gwak Eun Hye, Yoo Hee Young, Kim So Hee
College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon 16499, Republic of Korea.
Biomol Ther (Seoul). 2020 Jul 1;28(4):361-369. doi: 10.4062/biomolther.2020.006.
Tofacitinib, a Janus kinase inhibitor, was developed for the treatment of rheumatoid arthritis. Recently, it has been associated with an increased change in arthritis development in patients with diabetes. Herein, we evaluated the pharmacokinetics of tofacitinib after intravenous (10 mg/kg) and oral (20 mg/kg) administration to rats with streptozotocin-induced diabetes mellitus and control rats. Following intravenous administration of tofacitinib to rats with streptozotocin-induced diabetes mellitus, area under the plasma concentration-time curve from time zero to infinity of tofacitinib was significantly smaller (33.6%) than that of control rats. This might be due to the faster hepatic intrinsic clearance (112%) caused by an increase in the hepatic cytochrome P450 (CYP) 3A1(23) and the faster hepatic blood flow rate in rats with streptozotocin-induced diabetes mellitus than in control rats. Following oral administration, area under the plasma concentration-time curve from time zero to infinity of tofacitinib was also significantly smaller (55.5%) in rats with streptozotocin-induced diabetes mellitus than that in control rats. This might be due to decreased absorption caused by the higher expression of P-glycoprotein and the faster intestinal metabolism caused by the higher expression of intestinal CYP3A1(23), which resulted in the decreased bioavailability of tofacitinib (33.0%) in rats with streptozotocin-induced diabetes mellitus. In summary, our findings indicate that diabetes mellitus affects the absorption and metabolism of tofacitinib, causing faster metabolism and decreased intestinal absorption in rats with streptozotocin-induced diabetes mellitus.
托法替布是一种 Janus 激酶抑制剂，用于治疗类风湿性关节炎。最近，它与糖尿病患者关节炎发展的变化增加有关。在此，我们评估了托法替布在静脉注射（10 mg/kg）和口服（20 mg/kg）给药后，对链脲佐菌素诱导的糖尿病大鼠和对照大鼠的药代动力学。给链脲佐菌素诱导的糖尿病大鼠静脉注射托法替布后，托法替布从时间零到无穷大的血浆浓度 - 时间曲线下面积比对照大鼠显著更小（33.6%）。这可能是由于链脲佐菌素诱导的糖尿病大鼠中肝细胞色素 P450（CYP）3A1(23)增加导致肝内在清除率更快（112%），以及肝血流速度比对照大鼠更快。口服给药后,链脲佐菌素诱导的糖尿病大鼠中托法替布从时间零到无穷大的血浆浓度 - 时间曲线下面积也比对照大鼠显著更小（55.5%）。这可能是由于 P - 糖蛋白表达增加导致吸收减少，以及肠道 CYP3A1(23)表达增加导致肠道代谢更快，从而导致链脲佐菌素诱导的糖尿病大鼠中托法替布的生物利用度降低（33.0%）。总之，我们的研究结果表明，糖尿病会影响托法替布的吸收和代谢，导致链脲佐菌素诱导的糖尿病大鼠代谢加快和肠道吸收减少。
