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Preclinical Pharmacokinetic Studies of a Novel Diuretic Inhibiting Urea Transporters
Urea transporter (UT) inhibitors are a class of promising novel diuretics that do not cause the imbalance of Na(+), K(+), Cl(−), and other electrolytes. In our previous studies, 25a, a promising diuretic candidate inhibiting UT, was discovered and showed potent diuretic activities in rodents. Here,...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9027532/ https://www.ncbi.nlm.nih.gov/pubmed/35458649 http://dx.doi.org/10.3390/molecules27082451 |
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author | Xu, Yue Zhang, Hang Li, Nannan Ma, Wen Wang, Shuyuan Sun, Jianguo Yang, Baoxue |
author_facet | Xu, Yue Zhang, Hang Li, Nannan Ma, Wen Wang, Shuyuan Sun, Jianguo Yang, Baoxue |
author_sort | Xu, Yue |
collection | PubMed |
description | Urea transporter (UT) inhibitors are a class of promising novel diuretics that do not cause the imbalance of Na(+), K(+), Cl(−), and other electrolytes. In our previous studies, 25a, a promising diuretic candidate inhibiting UT, was discovered and showed potent diuretic activities in rodents. Here, a sensitive liquid chromatography–tandem mass spectrometry method for the quantitation of 25a in rat plasma, urine, feces, bile, and tissue homogenates was developed and validated to support the preclinical pharmacokinetic studies. The tissue distribution, excretion, and plasma protein binding were investigated in rats. After a single oral dose of 25a at 25, 50, and 100 mg/kg, the drug exposure increased linearly with the dose. The drug accumulation was observed after multiple oral doses compared to a single dose. In the distribution study, 25a exhibited a wide distribution to tissues with high blood perfusion, such as kidney, heart, lung, and spleen, and the lowest distribution in the brain and testis. The accumulative excretion rate of 25a was 0.14%, 3.16%, and 0.018% in urine, feces, and bile, respectively. The plasma protein binding of 25a was approximately 60% in rats and 40% in humans. This is the first study on the preclinical pharmacokinetic profiles of 25a. |
format | Online Article Text |
id | pubmed-9027532 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-90275322022-04-23 Preclinical Pharmacokinetic Studies of a Novel Diuretic Inhibiting Urea Transporters Xu, Yue Zhang, Hang Li, Nannan Ma, Wen Wang, Shuyuan Sun, Jianguo Yang, Baoxue Molecules Article Urea transporter (UT) inhibitors are a class of promising novel diuretics that do not cause the imbalance of Na(+), K(+), Cl(−), and other electrolytes. In our previous studies, 25a, a promising diuretic candidate inhibiting UT, was discovered and showed potent diuretic activities in rodents. Here, a sensitive liquid chromatography–tandem mass spectrometry method for the quantitation of 25a in rat plasma, urine, feces, bile, and tissue homogenates was developed and validated to support the preclinical pharmacokinetic studies. The tissue distribution, excretion, and plasma protein binding were investigated in rats. After a single oral dose of 25a at 25, 50, and 100 mg/kg, the drug exposure increased linearly with the dose. The drug accumulation was observed after multiple oral doses compared to a single dose. In the distribution study, 25a exhibited a wide distribution to tissues with high blood perfusion, such as kidney, heart, lung, and spleen, and the lowest distribution in the brain and testis. The accumulative excretion rate of 25a was 0.14%, 3.16%, and 0.018% in urine, feces, and bile, respectively. The plasma protein binding of 25a was approximately 60% in rats and 40% in humans. This is the first study on the preclinical pharmacokinetic profiles of 25a. MDPI 2022-04-11 /pmc/articles/PMC9027532/ /pubmed/35458649 http://dx.doi.org/10.3390/molecules27082451 Text en © 2022 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 Xu, Yue Zhang, Hang Li, Nannan Ma, Wen Wang, Shuyuan Sun, Jianguo Yang, Baoxue Preclinical Pharmacokinetic Studies of a Novel Diuretic Inhibiting Urea Transporters |
title | Preclinical Pharmacokinetic Studies of a Novel Diuretic Inhibiting Urea Transporters |
title_full | Preclinical Pharmacokinetic Studies of a Novel Diuretic Inhibiting Urea Transporters |
title_fullStr | Preclinical Pharmacokinetic Studies of a Novel Diuretic Inhibiting Urea Transporters |
title_full_unstemmed | Preclinical Pharmacokinetic Studies of a Novel Diuretic Inhibiting Urea Transporters |
title_short | Preclinical Pharmacokinetic Studies of a Novel Diuretic Inhibiting Urea Transporters |
title_sort | preclinical pharmacokinetic studies of a novel diuretic inhibiting urea transporters |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9027532/ https://www.ncbi.nlm.nih.gov/pubmed/35458649 http://dx.doi.org/10.3390/molecules27082451 |
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