UHPLC-MS/MS Assay for Quantification of Legubicin, a Novel Doxorubicin-Based Legumain-Activated Prodrug, and Its Application to Pharmacokinetic and Tissue Distribution Studies
Legubicin, a novel prodrug based on doxorubicin, has both albumin-binding and legumain-activating properties. The aim of this study was to develop and validate a UHPLC-MS/MS method for investigating the in vivo pharmacokinetics and tissue distribution profiles of legubicin in rats and tumor-bearing...
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| Format: | Article |
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MDPI AG
2024-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/29/4/775 |
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| author | Liyuan Ma Qiaoling Yu Meng Zhuang Chen Yang Yuan Liu Yuling Li Cheng Liu Xiaoyan Shen Yan Chang |
| author_facet | Liyuan Ma Qiaoling Yu Meng Zhuang Chen Yang Yuan Liu Yuling Li Cheng Liu Xiaoyan Shen Yan Chang |
| author_sort | Liyuan Ma |
| collection | DOAJ |
| description | Legubicin, a novel prodrug based on doxorubicin, has both albumin-binding and legumain-activating properties. The aim of this study was to develop and validate a UHPLC-MS/MS method for investigating the in vivo pharmacokinetics and tissue distribution profiles of legubicin in rats and tumor-bearing mice following intravenous administration, and to compare this prodrug with the positive control drug doxorubicin. The study employed a UHLC-MS/MS method to determine the levels of albumin-bound of legubicin and two metabolites (free Leu-DOX and DOX) in plasma, tumor, and tissue samples. This method was validated for good selectivity, high sensitivity, excellent extraction recovery, and short run time. The results showed that legubicin was present in the circulation in vivo mainly in a protein-bound form with larger AUC values and lower clearance and distribution, and essentially released small amounts of doxorubicin. Compared to administration of equimolar doses of doxorubicin, legubicin showed increased exposure of the active drug in the tumor and decreased the level of the active drug in the heart and kidney. This study provides valuable information on the pharmacokinetics and tissue distribution of legubicin, implicating its potential as a novel and effective drug candidate for anti-cancer therapies. |
| first_indexed | 2024-03-07T22:19:35Z |
| format | Article |
| id | doaj.art-254342e5e481427391ead5faecad38f4 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-07T22:19:35Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-254342e5e481427391ead5faecad38f42024-02-23T15:28:51ZengMDPI AGMolecules1420-30492024-02-0129477510.3390/molecules29040775UHPLC-MS/MS Assay for Quantification of Legubicin, a Novel Doxorubicin-Based Legumain-Activated Prodrug, and Its Application to Pharmacokinetic and Tissue Distribution StudiesLiyuan Ma0Qiaoling Yu1Meng Zhuang2Chen Yang3Yuan Liu4Yuling Li5Cheng Liu6Xiaoyan Shen7Yan Chang8Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, ChinaShanghai Innostar Bio-Tech Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, ChinaShanghai Innostar Bio-Tech Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, ChinaShanghai Innostar Bio-Tech Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, ChinaShanghai Affinity Bio-Pharmaceuticals Co., Ltd., Shanghai 201203, ChinaShanghai Affinity Bio-Pharmaceuticals Co., Ltd., Shanghai 201203, ChinaShanghai Affinity Bio-Pharmaceuticals Co., Ltd., Shanghai 201203, ChinaDepartment of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, ChinaShanghai Innostar Bio-Tech Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, ChinaLegubicin, a novel prodrug based on doxorubicin, has both albumin-binding and legumain-activating properties. The aim of this study was to develop and validate a UHPLC-MS/MS method for investigating the in vivo pharmacokinetics and tissue distribution profiles of legubicin in rats and tumor-bearing mice following intravenous administration, and to compare this prodrug with the positive control drug doxorubicin. The study employed a UHLC-MS/MS method to determine the levels of albumin-bound of legubicin and two metabolites (free Leu-DOX and DOX) in plasma, tumor, and tissue samples. This method was validated for good selectivity, high sensitivity, excellent extraction recovery, and short run time. The results showed that legubicin was present in the circulation in vivo mainly in a protein-bound form with larger AUC values and lower clearance and distribution, and essentially released small amounts of doxorubicin. Compared to administration of equimolar doses of doxorubicin, legubicin showed increased exposure of the active drug in the tumor and decreased the level of the active drug in the heart and kidney. This study provides valuable information on the pharmacokinetics and tissue distribution of legubicin, implicating its potential as a novel and effective drug candidate for anti-cancer therapies.https://www.mdpi.com/1420-3049/29/4/775doxorubicinLeu-DOXlegumainprodrugUHPLC-MS/MSpharmacokinetics |
| spellingShingle | Liyuan Ma Qiaoling Yu Meng Zhuang Chen Yang Yuan Liu Yuling Li Cheng Liu Xiaoyan Shen Yan Chang UHPLC-MS/MS Assay for Quantification of Legubicin, a Novel Doxorubicin-Based Legumain-Activated Prodrug, and Its Application to Pharmacokinetic and Tissue Distribution Studies Molecules doxorubicin Leu-DOX legumain prodrug UHPLC-MS/MS pharmacokinetics |
| title | UHPLC-MS/MS Assay for Quantification of Legubicin, a Novel Doxorubicin-Based Legumain-Activated Prodrug, and Its Application to Pharmacokinetic and Tissue Distribution Studies |
| title_full | UHPLC-MS/MS Assay for Quantification of Legubicin, a Novel Doxorubicin-Based Legumain-Activated Prodrug, and Its Application to Pharmacokinetic and Tissue Distribution Studies |
| title_fullStr | UHPLC-MS/MS Assay for Quantification of Legubicin, a Novel Doxorubicin-Based Legumain-Activated Prodrug, and Its Application to Pharmacokinetic and Tissue Distribution Studies |
| title_full_unstemmed | UHPLC-MS/MS Assay for Quantification of Legubicin, a Novel Doxorubicin-Based Legumain-Activated Prodrug, and Its Application to Pharmacokinetic and Tissue Distribution Studies |
| title_short | UHPLC-MS/MS Assay for Quantification of Legubicin, a Novel Doxorubicin-Based Legumain-Activated Prodrug, and Its Application to Pharmacokinetic and Tissue Distribution Studies |
| title_sort | uhplc ms ms assay for quantification of legubicin a novel doxorubicin based legumain activated prodrug and its application to pharmacokinetic and tissue distribution studies |
| topic | doxorubicin Leu-DOX legumain prodrug UHPLC-MS/MS pharmacokinetics |
| url | https://www.mdpi.com/1420-3049/29/4/775 |
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