Slower Elimination of Tofacitinib in Acute Renal Failure Rat Models: Contribution of Hepatic Metabolism and Renal Excretion

• Published in: Pharmaceutics 2020-07, Vol.12 (8), p.714
• Main Authors: Bae, Sung Hun, Chang, Sun-Young, Kim, So Hee
• Format: Article
• Language: English
• Subjects: acute renal failure; Carotid arteries; cisplatin; Creatinine; Drug dosages; FDA approval; gentamicin; hepatic CYP3A1; Kidney diseases; Laboratory animals; Metabolism; Mortality; Oral administration; Pharmaceuticals; Pharmacokinetics; Plasma; Polyethylene; Proteins; Rheumatoid arthritis; tofacitinib; Urine; Veins & arteries
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics12080714

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 CLR 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.