**Sung Hun Bae, Sun-Young Chang and So Hee Kim \***

Department of Pharmacy, College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Korea; baezzam@ajou.ac.kr (S.H.B.); sychang@ajou.ac.kr (S.-Y.C.)

**\*** Correspondence: shkim67@ajou.ac.kr; Tel.: +82-31-219-3451; Fax: +82-31-219-3435

Received: 29 June 2020; Accepted: 27 July 2020; Published: 30 July 2020

**Abstract:** 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 (CLR) was significantly lower by 69.5 and 98.6%, respectively, due to decreased creatinine clearance (CLCR). In addition, the time-averaged nonrenal clearance (CLNR) 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<sup>R</sup> and CLNR 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.

**Keywords:** tofacitinib; acute renal failure; gentamicin; cisplatin; pharmacokinetics; hepatic CYP3A1(23); creatinine clearance; renal clearance; nonrenal clearance
