Biomolecules & Therapeutics
Effects of Dextran Sulfate Sodium-Induced Ulcerative Colitis on the Disposition of Tofacitinib in Rats
Sung Hun Bae, Hyo Sung Kim, Hyeon Gyeom Choi, Sun-Young Chang and So Hee Kim*
College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon 16499, Republic of Korea
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Received: April 14, 2022; Revised: June 7, 2022; Accepted: June 9, 2022; Published online: July 11, 2022.
© The Korean Society of Applied Pharmacology. All rights reserved.

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Tofacitinib, a Janus kinase 1 and 3 inhibitor, is mainly metabolized by CYP3A1/2 and CYP2C11 in the liver. The drug has been approved for the chronic treatment of severe ulcerative colitis, a chronic inflammatory bowel disease. This study investigated the pharmacokinetics of tofacitinib in rats with dextran sulfate sodium (DSS)-induced ulcerative colitis. After 1-min of intravenous infusion of tofacitinib (10 mg/kg), the area under the plasma concentration-time curves from time zero to time infinity (AUC) of tofacitinib significantly increased by 92.3%. The time-averaged total body clearance decreased significantly by 47.7% in DSS rats compared with control rats. After the oral administration of tofacitinib (20 mg/kg), the AUC increased by 85.5% in DSS rats. These results could be due to decreased intrinsic clearance of the drug caused by the reduction of CYP3A1/2 and CYP2C11 in the liver and intestine of DSS rats. In conclusion, ulcerative colitis inhibited CYP3A1/2 and CYP2C11 in the liver and intestines of DSS rats and slowed the metabolism of tofacitinib, resulting in increased plasma concentrations of tofacitinib in DSS rats.
Keywords: Tofacitinib, Ulcerative colitis, Dextran sulfate sodium, Pharmacokinetics, CYP3A1/2, CYP2C11

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