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. 2020 Mar 25.
doi: 10.4062/biomolther.2020.006. Online ahead of print.

Effects of Diabetes Mellitus on the Disposition of Tofacitinib, a Janus Kinase Inhibitor, in Rats

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Effects of Diabetes Mellitus on the Disposition of Tofacitinib, a Janus Kinase Inhibitor, in Rats

Eun Hye Gwak et al. Biomol Ther (Seoul). .
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Abstract

Tofacitinib, a Janus kinase inhibitor, was developed for the treatment of rheumatoid arthritis. Recently, it has been associated withan increased change in arthritis development in patients with diabetes. Herein, we evaluated the pharmacokinetics of tofacitinibafter intravenous (10 mg/kg) and oral (20 mg/kg) administration to rats with streptozotocin-induced diabetes mellitus and controlrats. Following intravenous administration of tofacitinib to rats with streptozotocin-induced diabetes mellitus, area under theplasma 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. Followingoral administration, area under the plasma concentration-time curve from time zero to infinity of tofacitinib was also significantlysmaller (55.5%) in rats with streptozotocin-induced diabetes mellitus than that in control rats. This might be due to decreased absorptioncaused by the higher expression of P-glycoprotein and the faster intestinal metabolism caused by the higher expressionof intestinal CYP3A1(23), which resulted in the decreased bioavailability of tofacitinib (33.0%) in rats with streptozotocin-induceddiabetes 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.

Keywords: CYP3A1(23); Intrinsic clearance; P-pg; Pharmacokinetics; Streptozotocin-induced diabetes mellitus; Tofacitinib.

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