PEPT1-mediated prodrug strategy for oral delivery of peramivir
Peramivir was a novel and highly potent neuraminidase (NA) inhibitor for the treatment of influenza A and B. However, it exhibited a very low oral bioavailability (only 3%) due to the high polarity (log P of −1.4) and the low membrane permeability across the intestine. To utilize the PEPT1-mediated...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-11-01
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| Series: | Asian Journal of Pharmaceutical Sciences |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1818087618300308 |
| _version_ | 1828786213139513344 |
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| author | Yongbing Sun Wei Gan Mingdao Lei Wei Jiang Meng Cheng Junwei He Qi Sun Wan Liu Lvjiang Hu Yi Jin |
| author_facet | Yongbing Sun Wei Gan Mingdao Lei Wei Jiang Meng Cheng Junwei He Qi Sun Wan Liu Lvjiang Hu Yi Jin |
| author_sort | Yongbing Sun |
| collection | DOAJ |
| description | Peramivir was a novel and highly potent neuraminidase (NA) inhibitor for the treatment of influenza A and B. However, it exhibited a very low oral bioavailability (only 3%) due to the high polarity (log P of −1.4) and the low membrane permeability across the intestine. To utilize the PEPT1-mediated prodrug strategy to improve the oral absorption and develop the oral alternative, seven amino acid ester prodrugs and seven amino acid amide prodrugs have been synthesized. The permeability of these prodrugs across Caco-2 cells were screened. Peramivr-(CH2)2-l-Val and Peramivir-l-Ile were of the highest permeability in ester prodrugs and amide prodrugs, respectively, and then they were selected for further studies. Glycylsarcosine (gly-sar) uptake by Caco-2 could be inbihited by Peramivir-(CH2)2-l-Val and Peramivir-l-Ile in a concentration-dependent manner, and the IC50 was 1.34 ± 0.31 mM and 1.78 ± 0.48 mM, respectively. The direct uptake of Peramivir-(CH2)2-l-Val and Peramivir-l-Ile in MDCK-PEPT1 cells were significantly higher than in MDCK mock cells, and could be markedly inhibited by gly-sar. The uptake of Peramivir-(CH2)2-l-Val and Peramivir-l-Ile (0.01 to 50 mM) in MDCK-hPEPT1 cells conformed to Michaelis–Menten Equation. The oral bioavailability of peramivir was 65.3% and 37.3% after the oral administration of Peramivir-(CH2)2-l-Val and Peramivir-l-Ile to rats, respectively. The oral absorption and bioactivation of Peramivir-(CH2)2-l-Val was rapid and extensive, and no Peramivir-(CH2)2-l-Val was found in plasma. Because the amide bond was relatively stable, Peramivir-l-Ile could not be totally converted to the parent drug in vivo. Peramivir-(CH2)2-l-Val with good oral profiles and rapid bioactivation might be a promising prodrug for the further clinic development. The present study also corroborated the idea that the PEPT1-mediated prodrug approach has enormous promise for improving the oral absorption of poorly absorbed drug. Keywords: Peramivir, Prodrug, Peptide transporter 1, Pharmacokinetics, Oral bioavailability |
| first_indexed | 2024-12-12T00:06:05Z |
| format | Article |
| id | doaj.art-a761368037844daf9012ca980efcefd3 |
| institution | Directory Open Access Journal |
| issn | 1818-0876 |
| language | English |
| last_indexed | 2024-12-12T00:06:05Z |
| publishDate | 2018-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Asian Journal of Pharmaceutical Sciences |
| spelling | doaj.art-a761368037844daf9012ca980efcefd32022-12-22T00:45:06ZengElsevierAsian Journal of Pharmaceutical Sciences1818-08762018-11-01136555565PEPT1-mediated prodrug strategy for oral delivery of peramivirYongbing Sun0Wei Gan1Mingdao Lei2Wei Jiang3Meng Cheng4Junwei He5Qi Sun6Wan Liu7Lvjiang Hu8Yi Jin9Division of Pharmaceutics, National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, 56 Yangming Road, Nanchang 330006, ChinaDivision of Pharmaceutics, National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, 56 Yangming Road, Nanchang 330006, ChinaDepartment of Pharmacy, Jiangxi Maternal and Child Health Hospital, NO 318 Bayi Road, Nanchang 330001, ChinaResearch Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang 330004, ChinaDivision of Pharmaceutics, National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, 56 Yangming Road, Nanchang 330006, ChinaResearch Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang 330004, ChinaDivision of Pharmaceutics, National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, 56 Yangming Road, Nanchang 330006, ChinaDivision of Pharmaceutics, National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, 56 Yangming Road, Nanchang 330006, ChinaAffiliated Hospital of Jiangxi University of Traditional Chinese Medicine, NO 445 Bayi Road, Nanchang 330006, China; Corresponding author. Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, NO 445 Bayi Road, Nanchang 330006, China. Tel.: 86 791 87119652Division of Pharmaceutics, National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, 56 Yangming Road, Nanchang 330006, China; Corresponding author. Jiangxi University of Traditional Chinese Medicine, 56 Yangming Road, Nanchang 330006, China.Peramivir was a novel and highly potent neuraminidase (NA) inhibitor for the treatment of influenza A and B. However, it exhibited a very low oral bioavailability (only 3%) due to the high polarity (log P of −1.4) and the low membrane permeability across the intestine. To utilize the PEPT1-mediated prodrug strategy to improve the oral absorption and develop the oral alternative, seven amino acid ester prodrugs and seven amino acid amide prodrugs have been synthesized. The permeability of these prodrugs across Caco-2 cells were screened. Peramivr-(CH2)2-l-Val and Peramivir-l-Ile were of the highest permeability in ester prodrugs and amide prodrugs, respectively, and then they were selected for further studies. Glycylsarcosine (gly-sar) uptake by Caco-2 could be inbihited by Peramivir-(CH2)2-l-Val and Peramivir-l-Ile in a concentration-dependent manner, and the IC50 was 1.34 ± 0.31 mM and 1.78 ± 0.48 mM, respectively. The direct uptake of Peramivir-(CH2)2-l-Val and Peramivir-l-Ile in MDCK-PEPT1 cells were significantly higher than in MDCK mock cells, and could be markedly inhibited by gly-sar. The uptake of Peramivir-(CH2)2-l-Val and Peramivir-l-Ile (0.01 to 50 mM) in MDCK-hPEPT1 cells conformed to Michaelis–Menten Equation. The oral bioavailability of peramivir was 65.3% and 37.3% after the oral administration of Peramivir-(CH2)2-l-Val and Peramivir-l-Ile to rats, respectively. The oral absorption and bioactivation of Peramivir-(CH2)2-l-Val was rapid and extensive, and no Peramivir-(CH2)2-l-Val was found in plasma. Because the amide bond was relatively stable, Peramivir-l-Ile could not be totally converted to the parent drug in vivo. Peramivir-(CH2)2-l-Val with good oral profiles and rapid bioactivation might be a promising prodrug for the further clinic development. The present study also corroborated the idea that the PEPT1-mediated prodrug approach has enormous promise for improving the oral absorption of poorly absorbed drug. Keywords: Peramivir, Prodrug, Peptide transporter 1, Pharmacokinetics, Oral bioavailabilityhttp://www.sciencedirect.com/science/article/pii/S1818087618300308 |
| spellingShingle | Yongbing Sun Wei Gan Mingdao Lei Wei Jiang Meng Cheng Junwei He Qi Sun Wan Liu Lvjiang Hu Yi Jin PEPT1-mediated prodrug strategy for oral delivery of peramivir Asian Journal of Pharmaceutical Sciences |
| title | PEPT1-mediated prodrug strategy for oral delivery of peramivir |
| title_full | PEPT1-mediated prodrug strategy for oral delivery of peramivir |
| title_fullStr | PEPT1-mediated prodrug strategy for oral delivery of peramivir |
| title_full_unstemmed | PEPT1-mediated prodrug strategy for oral delivery of peramivir |
| title_short | PEPT1-mediated prodrug strategy for oral delivery of peramivir |
| title_sort | pept1 mediated prodrug strategy for oral delivery of peramivir |
| url | http://www.sciencedirect.com/science/article/pii/S1818087618300308 |
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