Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.006
Effects of Diabetes Mellitus on the Disposition of Tofacitinib, a Janus Kinase Inhibitor, in Rats
Eun Hye Gwak, Hee Young Yoo and So Hee Kim*
College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon 16499, Republic of Korea
E-mail: shkim67@ajou.ac.kr
Tel: +82-31-219-3451, Fax: +82-31-219-3435
Received: January 16, 2020; Revised: February 14, 2020; Accepted: February 21, 2020; Published online: March 25, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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: Tofacitinib, CYP3A1(23), Streptozotocin-induced diabetes mellitus, P-pg, Intrinsic clearance, Pharmacokinetics


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