Tofacitinib is a Jak inhibitor developed as a treatment for rheumatoid arthritis. Tofacitinib is metabolized mainly through hepatic CYP3A1/2, followed by CYP2C11. Rheumatoid arthritis tends to increase renal toxicity due to drugs used for long-term treatment. In this study, pharmacokinetic changes of tofacitinib were evaluated in rats with gentamicin (G-ARF) and cisplatin-induced acute renal failure (C-ARF). The time-averaged total body clearance (CL) of tofacitinib in G-ARF and C-ARF rats after 1-min intravenous infusion of 10 mg/kg was significantly decreased by 37.7 and 62.3%, respectively, compared to in control rats. This seems to be because the time-averaged renal clearance (CL_R) was significantly lower by 69.5 and 98.6%, respectively, due to decreased creatinine clearance (CL_CR). In addition, the time-averaged nonrenal clearance (CL_NR) was also significantly lower by 33.2 and 57.4%, respectively, due to reduction in the hepatic CYP3A1/2 and CYP2C11 subfamily in G-ARF and C-ARF rats. After oral administration of tofacitinib (20 mg/kg) to G-ARF and C-ARF rats, both CL_R and CL_NR were also significantly decreased. In conclusion, an increase in area under plasma concentration-time curves from time zero to time infinity (AUC) of tofacitinib in G-ARF and C-ARF rats was due to the significantly slower elimination of tofacitinib contributed by slower hepatic metabolism and urinary excretion of the drug.

中文翻译：

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急性肾功能衰竭大鼠模型中Tofacitinib的缓慢消除：肝代谢和肾脏排泄的贡献。

Tofacitinib是开发用于治疗类风湿关节炎的Jak抑制剂。Tofacitinib主要通过肝脏CYP3A1 / 2代谢，随后通过CYP2C11代谢。由于用于长期治疗的药物，类风湿关节炎倾向于增加肾脏毒性。在这项研究中，评价了庆大霉素（G-ARF）和顺铂诱导的急性肾衰竭（C-ARF）大鼠的托法替尼药代动力学变化。与对照组相比，G-ARF和C-ARF大鼠在1分钟静脉输注10 mg / kg后，托法替尼的平均时空清除率（CL）分别显着降低了37.7和62.3％。这似乎是因为时间平均肾清除率（CL _R）分别由于肌酐清除率（CL _CR）的降低而显着降低了69.5和98.6％。）。此外，由于G-ARF和C-ARF大鼠肝CYP3A1 / 2和CYP2C11亚家族的减少，非肾脏平均时间清除率（CL _NR）也分别显着降低了33.2％和57.4％。在G-ARF和C-ARF大鼠口服托法替尼（20 mg / kg）后，CL _R和CL _NR均显着降低。总之，在G-ARF和C-ARF大鼠中，托法替尼的血浆浓度-时间曲线下面积从零时到无限时（AUC）的增加是由于肝脏代谢和尿液排泄减慢而导致的Tofacitinib的清除明显减慢。的药物。