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Effects of Hyperlipidemia on the Pharmacokinetics of Tofacitinib, a JAK 1/3 Inhibitor, in Rats
Tofacitinib, an inhibitor of Janus kinases (JAKs) 1 and 3, has been shown to be effective in the treatment of rheumatoid arthritis. The incidence of hyperlipidemia has been found to be higher in patients with rheumatoid arthritis. The present study therefore investigated the pharmacokinetics of tofa...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10534486/ https://www.ncbi.nlm.nih.gov/pubmed/37765165 http://dx.doi.org/10.3390/pharmaceutics15092195 |
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author | Won, Jong Mun Choi, Hyeon Gyeom Park, So Yeon Kim, Jang-Hee Kim, So Hee |
author_facet | Won, Jong Mun Choi, Hyeon Gyeom Park, So Yeon Kim, Jang-Hee Kim, So Hee |
author_sort | Won, Jong Mun |
collection | PubMed |
description | Tofacitinib, an inhibitor of Janus kinases (JAKs) 1 and 3, has been shown to be effective in the treatment of rheumatoid arthritis. The incidence of hyperlipidemia has been found to be higher in patients with rheumatoid arthritis. The present study therefore investigated the pharmacokinetics of tofacitinib after its intravenous (10 mg/kg) or oral (20 mg/kg) administration in poloxamer-407-induced hyperlipidemic (PHL) rats. The area under the plasma concentration-time curve from zero to infinity (AUC(0–∞)) after intravenous administration of tofacitinib was 73.5% higher in PHL than in control rats, owing to slower time-averaged nonrenal clearance (CL(NR)) in the former. Evaluation of in vitro metabolism showed that the intrinsic clearance (CL(int)) of tofacitinib was 38.6% lower in PHL than in control rats, owing to the decreased protein expression of hepatic cytochrome P450 (CYP) 3A1/2 and CYP2C11 in PHL rats. Similar results were observed in PHL rats after oral administration of tofacitinib. These results were likely due to the decreased CL(NR), CL(int), and P-glycoprotein (P-gp) expression in the intestines of PHL compared to control rats. Overall, these findings indicated that hyperlipidemia slowed the metabolism of tofacitinib, increasing its plasma concentrations, and that this reduced metabolism was due to alterations in expression of the proteins CYP3A1/2, CYP2C11, and P-gp in the liver and/or intestines of PHL rats. |
format | Online Article Text |
id | pubmed-10534486 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-105344862023-09-29 Effects of Hyperlipidemia on the Pharmacokinetics of Tofacitinib, a JAK 1/3 Inhibitor, in Rats Won, Jong Mun Choi, Hyeon Gyeom Park, So Yeon Kim, Jang-Hee Kim, So Hee Pharmaceutics Article Tofacitinib, an inhibitor of Janus kinases (JAKs) 1 and 3, has been shown to be effective in the treatment of rheumatoid arthritis. The incidence of hyperlipidemia has been found to be higher in patients with rheumatoid arthritis. The present study therefore investigated the pharmacokinetics of tofacitinib after its intravenous (10 mg/kg) or oral (20 mg/kg) administration in poloxamer-407-induced hyperlipidemic (PHL) rats. The area under the plasma concentration-time curve from zero to infinity (AUC(0–∞)) after intravenous administration of tofacitinib was 73.5% higher in PHL than in control rats, owing to slower time-averaged nonrenal clearance (CL(NR)) in the former. Evaluation of in vitro metabolism showed that the intrinsic clearance (CL(int)) of tofacitinib was 38.6% lower in PHL than in control rats, owing to the decreased protein expression of hepatic cytochrome P450 (CYP) 3A1/2 and CYP2C11 in PHL rats. Similar results were observed in PHL rats after oral administration of tofacitinib. These results were likely due to the decreased CL(NR), CL(int), and P-glycoprotein (P-gp) expression in the intestines of PHL compared to control rats. Overall, these findings indicated that hyperlipidemia slowed the metabolism of tofacitinib, increasing its plasma concentrations, and that this reduced metabolism was due to alterations in expression of the proteins CYP3A1/2, CYP2C11, and P-gp in the liver and/or intestines of PHL rats. MDPI 2023-08-24 /pmc/articles/PMC10534486/ /pubmed/37765165 http://dx.doi.org/10.3390/pharmaceutics15092195 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Won, Jong Mun Choi, Hyeon Gyeom Park, So Yeon Kim, Jang-Hee Kim, So Hee Effects of Hyperlipidemia on the Pharmacokinetics of Tofacitinib, a JAK 1/3 Inhibitor, in Rats |
title | Effects of Hyperlipidemia on the Pharmacokinetics of Tofacitinib, a JAK 1/3 Inhibitor, in Rats |
title_full | Effects of Hyperlipidemia on the Pharmacokinetics of Tofacitinib, a JAK 1/3 Inhibitor, in Rats |
title_fullStr | Effects of Hyperlipidemia on the Pharmacokinetics of Tofacitinib, a JAK 1/3 Inhibitor, in Rats |
title_full_unstemmed | Effects of Hyperlipidemia on the Pharmacokinetics of Tofacitinib, a JAK 1/3 Inhibitor, in Rats |
title_short | Effects of Hyperlipidemia on the Pharmacokinetics of Tofacitinib, a JAK 1/3 Inhibitor, in Rats |
title_sort | effects of hyperlipidemia on the pharmacokinetics of tofacitinib, a jak 1/3 inhibitor, in rats |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10534486/ https://www.ncbi.nlm.nih.gov/pubmed/37765165 http://dx.doi.org/10.3390/pharmaceutics15092195 |
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