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L-Type Amino Acid Transporter 1-Utilizing Prodrugs of Ketoprofen Can Efficiently Reduce Brain Prostaglandin Levels
In order to efficiently combat neuroinflammation, it is essential to deliver the anti-inflammatory drugs to their target sites in the brain. Pro-drugs utilizing the L-type amino acid transporter 1 (LAT1) can be transported across the blood-brain barrier (BBB) and the cellular barriers of the brain’s...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238114/ https://www.ncbi.nlm.nih.gov/pubmed/32290494 http://dx.doi.org/10.3390/pharmaceutics12040344 |
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author | Montaser, Ahmed Lehtonen, Marko Gynther, Mikko Huttunen, Kristiina M. |
author_facet | Montaser, Ahmed Lehtonen, Marko Gynther, Mikko Huttunen, Kristiina M. |
author_sort | Montaser, Ahmed |
collection | PubMed |
description | In order to efficiently combat neuroinflammation, it is essential to deliver the anti-inflammatory drugs to their target sites in the brain. Pro-drugs utilizing the L-type amino acid transporter 1 (LAT1) can be transported across the blood-brain barrier (BBB) and the cellular barriers of the brain’s parenchymal cells. In this study, we evaluated, for the first time, the efficacy of LAT1-utilizing prodrugs of ketoprofen (KPF) on cyclooxygenase (COX) enzymes in vitro and prostaglandin E2 production in vivo by using an enzymatic assay and liquid chromatography- tandem mass spectrometry method, respectively. Aliphatic amino acid-conjugated pro-drugs inhibited the peroxidase activity of COX in vitro in their intact form (85% inhibition, IC50 ≈ 1.1 µM and 79%, IC50 ≈ 2.3 µM), which was comparable to KPF (90%, IC50 ≈ 0.9). Thus, these compounds acted more as KPF derivatives rather than pro-drugs. In turn, aromatic amino acid-conjugated pro-drugs behaved differently. The ester pro-drug inhibited the COX peroxidase activity in vitro (90%, IC50 ≈ 0.6 µM) due to its bioconversion to KPF, whereas the amide pro-drug was inactive toward COX enzymes in vitro. However, the amide pro-drug released KPF in the mouse brain in sufficient and effective amounts measured as reduced PGE2 levels. |
format | Online Article Text |
id | pubmed-7238114 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-72381142020-05-28 L-Type Amino Acid Transporter 1-Utilizing Prodrugs of Ketoprofen Can Efficiently Reduce Brain Prostaglandin Levels Montaser, Ahmed Lehtonen, Marko Gynther, Mikko Huttunen, Kristiina M. Pharmaceutics Article In order to efficiently combat neuroinflammation, it is essential to deliver the anti-inflammatory drugs to their target sites in the brain. Pro-drugs utilizing the L-type amino acid transporter 1 (LAT1) can be transported across the blood-brain barrier (BBB) and the cellular barriers of the brain’s parenchymal cells. In this study, we evaluated, for the first time, the efficacy of LAT1-utilizing prodrugs of ketoprofen (KPF) on cyclooxygenase (COX) enzymes in vitro and prostaglandin E2 production in vivo by using an enzymatic assay and liquid chromatography- tandem mass spectrometry method, respectively. Aliphatic amino acid-conjugated pro-drugs inhibited the peroxidase activity of COX in vitro in their intact form (85% inhibition, IC50 ≈ 1.1 µM and 79%, IC50 ≈ 2.3 µM), which was comparable to KPF (90%, IC50 ≈ 0.9). Thus, these compounds acted more as KPF derivatives rather than pro-drugs. In turn, aromatic amino acid-conjugated pro-drugs behaved differently. The ester pro-drug inhibited the COX peroxidase activity in vitro (90%, IC50 ≈ 0.6 µM) due to its bioconversion to KPF, whereas the amide pro-drug was inactive toward COX enzymes in vitro. However, the amide pro-drug released KPF in the mouse brain in sufficient and effective amounts measured as reduced PGE2 levels. MDPI 2020-04-11 /pmc/articles/PMC7238114/ /pubmed/32290494 http://dx.doi.org/10.3390/pharmaceutics12040344 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Montaser, Ahmed Lehtonen, Marko Gynther, Mikko Huttunen, Kristiina M. L-Type Amino Acid Transporter 1-Utilizing Prodrugs of Ketoprofen Can Efficiently Reduce Brain Prostaglandin Levels |
title | L-Type Amino Acid Transporter 1-Utilizing Prodrugs of Ketoprofen Can Efficiently Reduce Brain Prostaglandin Levels |
title_full | L-Type Amino Acid Transporter 1-Utilizing Prodrugs of Ketoprofen Can Efficiently Reduce Brain Prostaglandin Levels |
title_fullStr | L-Type Amino Acid Transporter 1-Utilizing Prodrugs of Ketoprofen Can Efficiently Reduce Brain Prostaglandin Levels |
title_full_unstemmed | L-Type Amino Acid Transporter 1-Utilizing Prodrugs of Ketoprofen Can Efficiently Reduce Brain Prostaglandin Levels |
title_short | L-Type Amino Acid Transporter 1-Utilizing Prodrugs of Ketoprofen Can Efficiently Reduce Brain Prostaglandin Levels |
title_sort | l-type amino acid transporter 1-utilizing prodrugs of ketoprofen can efficiently reduce brain prostaglandin levels |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238114/ https://www.ncbi.nlm.nih.gov/pubmed/32290494 http://dx.doi.org/10.3390/pharmaceutics12040344 |
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