Effects of Isosakuranetin on Pharmacokinetic Changes of Tofacitinib in Rats with <i>N</i>-Dimethylnitrosamine-Induced Liver Cirrhosis
Tofacitinib, a Janus kinase 1 and 3 inhibitor, is used to treat rheumatoid arthritis. It is mainly metabolized by the cytochromes p450 (CYP) 3A1/2 and CYP2C11 in the liver. Chronic inflammation eventually leads to cirrhosis in patients with rheumatoid arthritis. Isosakuranetin (ISN), a component of...
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MDPI AG
2022-12-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/12/2684 |
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| author | Sung Hun Bae Hyeon Gyeom Choi So Yeon Park Sun-Young Chang Hyoungsu Kim So Hee Kim |
| author_facet | Sung Hun Bae Hyeon Gyeom Choi So Yeon Park Sun-Young Chang Hyoungsu Kim So Hee Kim |
| author_sort | Sung Hun Bae |
| collection | DOAJ |
| description | Tofacitinib, a Janus kinase 1 and 3 inhibitor, is used to treat rheumatoid arthritis. It is mainly metabolized by the cytochromes p450 (CYP) 3A1/2 and CYP2C11 in the liver. Chronic inflammation eventually leads to cirrhosis in patients with rheumatoid arthritis. Isosakuranetin (ISN), a component of <i>Citrus aurantium</i> L., has hepatoprotective effects in rats. This study was performed to determine the effects of ISN on the pharmacokinetics of tofacitinib in rats with <i>N</i>-dimethylnitrosamine-induced liver cirrhosis (LC). After intravenous administration of 10 mg/kg tofacitinib to control (CON), LC, and LC treated with ISN (LC-ISN) rats, the total area under the plasma concentration–time curves (AUC) from time zero to infinity increased by 158% in LC rats compared to those in CON rats; however, the AUC of LC-ISN rats decreased by 35.1% compared to that of LC rat. Similar patterns of AUC changes were observed in the LC and LC-ISN rats after oral administration of 20 mg/kg tofacitinib. These results can be attributed to decreased non-renal clearance (CL<sub>NR</sub>) and intestinal intrinsic clearance (CL<sub>int</sub>) in the LC rats and increased intestinal and hepatic CL<sub>int</sub> in the LC-ISN rats. Our findings imply that ISN treatment in LC rats restored the decrease in either CL<sub>NR</sub> or CL<sub>int</sub>, or both, through increased hepatic and intestinal expression of CYP3A1/2 and CYP2C11, which is regulated by the induction of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). |
| first_indexed | 2024-03-09T15:58:55Z |
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| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T15:58:55Z |
| publishDate | 2022-12-01 |
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| series | Pharmaceutics |
| spelling | doaj.art-fe33308a8e25453a8c041e668fe8419d2023-11-24T17:20:12ZengMDPI AGPharmaceutics1999-49232022-12-011412268410.3390/pharmaceutics14122684Effects of Isosakuranetin on Pharmacokinetic Changes of Tofacitinib in Rats with <i>N</i>-Dimethylnitrosamine-Induced Liver CirrhosisSung Hun Bae0Hyeon Gyeom Choi1So Yeon Park2Sun-Young Chang3Hyoungsu Kim4So Hee Kim5College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of KoreaCollege of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of KoreaDepartment of Biohealth Regulatory Science, Graduate School of Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of KoreaCollege of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of KoreaCollege of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of KoreaCollege of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of KoreaTofacitinib, a Janus kinase 1 and 3 inhibitor, is used to treat rheumatoid arthritis. It is mainly metabolized by the cytochromes p450 (CYP) 3A1/2 and CYP2C11 in the liver. Chronic inflammation eventually leads to cirrhosis in patients with rheumatoid arthritis. Isosakuranetin (ISN), a component of <i>Citrus aurantium</i> L., has hepatoprotective effects in rats. This study was performed to determine the effects of ISN on the pharmacokinetics of tofacitinib in rats with <i>N</i>-dimethylnitrosamine-induced liver cirrhosis (LC). After intravenous administration of 10 mg/kg tofacitinib to control (CON), LC, and LC treated with ISN (LC-ISN) rats, the total area under the plasma concentration–time curves (AUC) from time zero to infinity increased by 158% in LC rats compared to those in CON rats; however, the AUC of LC-ISN rats decreased by 35.1% compared to that of LC rat. Similar patterns of AUC changes were observed in the LC and LC-ISN rats after oral administration of 20 mg/kg tofacitinib. These results can be attributed to decreased non-renal clearance (CL<sub>NR</sub>) and intestinal intrinsic clearance (CL<sub>int</sub>) in the LC rats and increased intestinal and hepatic CL<sub>int</sub> in the LC-ISN rats. Our findings imply that ISN treatment in LC rats restored the decrease in either CL<sub>NR</sub> or CL<sub>int</sub>, or both, through increased hepatic and intestinal expression of CYP3A1/2 and CYP2C11, which is regulated by the induction of pregnane X receptor (PXR) and constitutive androstane receptor (CAR).https://www.mdpi.com/1999-4923/14/12/2684tofacitinibliver cirrhosisisosakuranetinpharmacokineticsCYP3A1/2CYP2C11 |
| spellingShingle | Sung Hun Bae Hyeon Gyeom Choi So Yeon Park Sun-Young Chang Hyoungsu Kim So Hee Kim Effects of Isosakuranetin on Pharmacokinetic Changes of Tofacitinib in Rats with <i>N</i>-Dimethylnitrosamine-Induced Liver Cirrhosis Pharmaceutics tofacitinib liver cirrhosis isosakuranetin pharmacokinetics CYP3A1/2 CYP2C11 |
| title | Effects of Isosakuranetin on Pharmacokinetic Changes of Tofacitinib in Rats with <i>N</i>-Dimethylnitrosamine-Induced Liver Cirrhosis |
| title_full | Effects of Isosakuranetin on Pharmacokinetic Changes of Tofacitinib in Rats with <i>N</i>-Dimethylnitrosamine-Induced Liver Cirrhosis |
| title_fullStr | Effects of Isosakuranetin on Pharmacokinetic Changes of Tofacitinib in Rats with <i>N</i>-Dimethylnitrosamine-Induced Liver Cirrhosis |
| title_full_unstemmed | Effects of Isosakuranetin on Pharmacokinetic Changes of Tofacitinib in Rats with <i>N</i>-Dimethylnitrosamine-Induced Liver Cirrhosis |
| title_short | Effects of Isosakuranetin on Pharmacokinetic Changes of Tofacitinib in Rats with <i>N</i>-Dimethylnitrosamine-Induced Liver Cirrhosis |
| title_sort | effects of isosakuranetin on pharmacokinetic changes of tofacitinib in rats with i n i dimethylnitrosamine induced liver cirrhosis |
| topic | tofacitinib liver cirrhosis isosakuranetin pharmacokinetics CYP3A1/2 CYP2C11 |
| url | https://www.mdpi.com/1999-4923/14/12/2684 |
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