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Purpose <p>Tofacitinib, a Janus kinase inhibitor, is metabolized by hepatic cytochrome P450 enzymes. Isosakuranetin (ISN), a citrus-derived flavonoid, has reported antioxidant and anti-inflammatory effects. This study assessed ISN’s glucose-lowering action and its impact on tofacitinib pharmacokinetics in streptozotocin (STZ)-induced diabetic rats.</p> Methods <p>Tofacitinib was given intravenously (10 mg/kg) or orally (20 mg/kg) to control (CON), ISN, diabetic (DM), and DM treated with ISN (DM-ISN) groups. DM was induced by STZ (60 mg/kg, i.p.). ISN (15 mg/kg) was administered orally for 14 days. Liver/kidney function and microsomal metabolism were evaluated.</p> Results <p>In DM rats, both intravenous and oral administration of tofacitinib significantly increased the area under the plasma concentration-time curve from time 0 to infinity (AUC) by 179% and 97.3%, respectively, with a 63.8% reduction in nonrenal clearance (CLNR). Intrinsic clearance (CLint) decreased by 22% in liver and 61.2% in intestine, and hepatic CYP2C expression fell by 66.1% compared to CON rats. In DM-ISN rats, blood glucose was reduced and pharmacokinetic parameters (AUC and CLs) approximated CON levels. Compared with DM, DM-ISN rats showed hepatic and intestinal CLint increases of 27.8% and 93.7%, respectively, and hepatic CYP2C expression rose by 17.4%. Liver and renal biomarkers were also improved in DM-ISN rats.</p> Conclusion <p>ISN lowered glucose and partially restored CYP-mediated metabolic capacity in diabetic rats, reversing tofacitinib pharmacokinetic alterations; these preclinical findings warrant consideration in future studies of herb-drug interactions under diabetic conditions.</p>

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Modulation of tofacitinib pharmacokinetics by isosakuranetin in streptozotocin-induced diabetic rats

  • 期刊论文

  • 发表日期：

    2025年12月23日

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  • Hyeon Gyeom Choi,
  • Sung Hun Bae,
  • So Yeon Park,
  • Hyoungsu Kim,
  • Sun-Young Chang,
  • So Hee Kim

摘要

Purpose

Tofacitinib, a Janus kinase inhibitor, is metabolized by hepatic cytochrome P450 enzymes. Isosakuranetin (ISN), a citrus-derived flavonoid, has reported antioxidant and anti-inflammatory effects. This study assessed ISN’s glucose-lowering action and its impact on tofacitinib pharmacokinetics in streptozotocin (STZ)-induced diabetic rats.

Methods

Tofacitinib was given intravenously (10 mg/kg) or orally (20 mg/kg) to control (CON), ISN, diabetic (DM), and DM treated with ISN (DM-ISN) groups. DM was induced by STZ (60 mg/kg, i.p.). ISN (15 mg/kg) was administered orally for 14 days. Liver/kidney function and microsomal metabolism were evaluated.

Results

In DM rats, both intravenous and oral administration of tofacitinib significantly increased the area under the plasma concentration-time curve from time 0 to infinity (AUC) by 179% and 97.3%, respectively, with a 63.8% reduction in nonrenal clearance (CLNR). Intrinsic clearance (CLint) decreased by 22% in liver and 61.2% in intestine, and hepatic CYP2C expression fell by 66.1% compared to CON rats. In DM-ISN rats, blood glucose was reduced and pharmacokinetic parameters (AUC and CLs) approximated CON levels. Compared with DM, DM-ISN rats showed hepatic and intestinal CLint increases of 27.8% and 93.7%, respectively, and hepatic CYP2C expression rose by 17.4%. Liver and renal biomarkers were also improved in DM-ISN rats.

Conclusion

ISN lowered glucose and partially restored CYP-mediated metabolic capacity in diabetic rats, reversing tofacitinib pharmacokinetic alterations; these preclinical findings warrant consideration in future studies of herb-drug interactions under diabetic conditions.