Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Effects of Dextran Sulfate Sodium-Induced Ulcerative Colitis on the Disposition of Tofacitinib in Rats

  • Bae, Sung Hun (College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University) ;
  • Kim, Hyo Sung (College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University) ;
  • Choi, Hyeon Gyeom (College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University) ;
  • Chang, Sun-Young (College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University) ;
  • Kim, So Hee (College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University)
  • Received : 2022.04.14
  • Accepted : 2022.06.09
  • Published : 2022.11.01
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Abstract

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

Acknowledgement

This work was supported by Basic Science Research Program (NRF-2021R1A2C1011142) through the National Research Foundation of Korea grant funded by the Ministry of Science and ICT, Republic of Korea.

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