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

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 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.

Effects of Dextran Sulfate Sodium-Induced Ulcerative Colitis on the Disposition of Tofacitinib in Rats

“…To estimate creatinine clearance (CL CR ), urine samples were collected for 24 h and urine volumes and creatinine levels were measured. CL CR was estimated by dividing the amount of creatinine excreted in the urine over 24 h by the area under the plasma concentration-time curve of creatinine from 0 to 24 h (AUC 0-24 h ) ( Bae et al ., 2020 ). For tissue biopsies, whole kidneys and livers were removed from CON and DSS rats and weighed.…”

“…The experiments were conducted as previously reported ( Bae et al ., 2020 ; Gwak et al ., 2020 ) for the preparation of hepatic and intestinal microsomes. Protein concentrations of hepatic and intestinal microsomes were estimated using the bicinchoninic acid method.…”

“…Protein expression was visualized by enhanced chemiluminescence (Bio-Rad) using an Image Quant LAS 4000 Mini (GE Healthcare Life Sciences, Piscataway, NJ, USA) and band density was measured using ImageJ 1.45s software (NIH, Bethesda, MA, USA). β-Actin was used as an internal standard ( Bae et al ., 2020 ).…”

“…In a rat model of cisplatin-induced acute renal failure, renal excretion of tofacitinib was significantly reduced owing to the deterioration of renal function. Additionally, drug metabolism was also reduced due to a significant decrease in hepatic CYP3A1/2 after intravenous and oral administration of tofacitinib, which resulted in an increased plasma concentration of tofacitinib ( Bae et al ., 2020 ).…”

Pharmacokinetic Drug Interaction between Tofacitinib and Voriconazole in Rats

“…Protein expression was visualized using enhanced chemiluminescence (Bio-Rad) and captured by an Image Quant LAS 4000 Mini (GE Healthcare Life Sciences, Piscataway, NJ, USA). The expression of β-actin was used as the internal standard [ 21 , 31 ]. The band density was measured and compared using ImageJ 1.45 s software (NIH, Bethesda, MA, USA).…”