Investigation of the GnRH antagonist degarelix isomerization in biological matrices
One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by the complex modifications of the primary structure of the peptides. However, these changes often lead to the formation of peculiar impuritie...
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Published in | Pharmacology research & perspectives Vol. 11; no. 4; pp. e01117 - n/a |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
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United States
John Wiley & Sons, Inc
01.08.2023
John Wiley and Sons Inc Wiley |
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Abstract | One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by the complex modifications of the primary structure of the peptides. However, these changes often lead to the formation of peculiar impurities in the peptide drugs and their metabolites, which require the development of advanced analytical methods to properly assess their content. Here, we investigated the degradation of the potent long‐acting GnRH antagonist degarelix in various biologic media by the tailor‐made HPLC method, which allows precise determination of 5‐Aph(Hyd)‐degarelix isomer, an impurity found in the degarelix active pharmaceutical ingredient (API) during its manufacturing. Unexpectedly, we discovered a rapid and irreversible conversion of degarelix API into the corresponding hydantoin isomer in serum, suggesting that this impurity can be also a potential drug metabolite in vivo. This finding underlines the importance of the development of more accurate and performing analytical techniques to correctly characterize the chemical composition of the manufactured drugs and their behavior under physiological conditions.
We investigated the degradation of the GnRH antagonist Degarelix in various biologic media by the tailor‐made HPLC method, which allows precise determination of 5‐Aph(Hyd)‐Degarelix isomer, and we discovered a rapid and irreversible conversion of Degarelix API into the corresponding hydantoin isomer in serum, suggesting that it can be a potential drug metabolite in vivo. This finding can improve the understanding of the metabolic pathways of Degarelix. |
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AbstractList | One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by the complex modifications of the primary structure of the peptides. However, these changes often lead to the formation of peculiar impurities in the peptide drugs and their metabolites, which require the development of advanced analytical methods to properly assess their content. Here, we investigated the degradation of the potent long-acting GnRH antagonist degarelix in various biologic media by the tailor-made HPLC method, which allows precise determination of 5-Aph(Hyd)-degarelix isomer, an impurity found in the degarelix active pharmaceutical ingredient (API) during its manufacturing. Unexpectedly, we discovered a rapid and irreversible conversion of degarelix API into the corresponding hydantoin isomer in serum, suggesting that this impurity can be also a potential drug metabolite in vivo. This finding underlines the importance of the development of more accurate and performing analytical techniques to correctly characterize the chemical composition of the manufactured drugs and their behavior under physiological conditions. Abstract One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by the complex modifications of the primary structure of the peptides. However, these changes often lead to the formation of peculiar impurities in the peptide drugs and their metabolites, which require the development of advanced analytical methods to properly assess their content. Here, we investigated the degradation of the potent long‐acting GnRH antagonist degarelix in various biologic media by the tailor‐made HPLC method, which allows precise determination of 5‐Aph(Hyd)‐degarelix isomer, an impurity found in the degarelix active pharmaceutical ingredient (API) during its manufacturing. Unexpectedly, we discovered a rapid and irreversible conversion of degarelix API into the corresponding hydantoin isomer in serum, suggesting that this impurity can be also a potential drug metabolite in vivo. This finding underlines the importance of the development of more accurate and performing analytical techniques to correctly characterize the chemical composition of the manufactured drugs and their behavior under physiological conditions. One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by the complex modifications of the primary structure of the peptides. However, these changes often lead to the formation of peculiar impurities in the peptide drugs and their metabolites, which require the development of advanced analytical methods to properly assess their content. Here, we investigated the degradation of the potent long‐acting GnRH antagonist degarelix in various biologic media by the tailor‐made HPLC method, which allows precise determination of 5‐Aph(Hyd)‐degarelix isomer, an impurity found in the degarelix active pharmaceutical ingredient (API) during its manufacturing. Unexpectedly, we discovered a rapid and irreversible conversion of degarelix API into the corresponding hydantoin isomer in serum, suggesting that this impurity can be also a potential drug metabolite in vivo. This finding underlines the importance of the development of more accurate and performing analytical techniques to correctly characterize the chemical composition of the manufactured drugs and their behavior under physiological conditions. We investigated the degradation of the GnRH antagonist Degarelix in various biologic media by the tailor‐made HPLC method, which allows precise determination of 5‐Aph(Hyd)‐Degarelix isomer, and we discovered a rapid and irreversible conversion of Degarelix API into the corresponding hydantoin isomer in serum, suggesting that it can be a potential drug metabolite in vivo. This finding can improve the understanding of the metabolic pathways of Degarelix. Abstract One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by the complex modifications of the primary structure of the peptides. However, these changes often lead to the formation of peculiar impurities in the peptide drugs and their metabolites, which require the development of advanced analytical methods to properly assess their content. Here, we investigated the degradation of the potent long‐acting GnRH antagonist degarelix in various biologic media by the tailor‐made HPLC method, which allows precise determination of 5‐Aph(Hyd)‐degarelix isomer, an impurity found in the degarelix active pharmaceutical ingredient (API) during its manufacturing. Unexpectedly, we discovered a rapid and irreversible conversion of degarelix API into the corresponding hydantoin isomer in serum, suggesting that this impurity can be also a potential drug metabolite in vivo. This finding underlines the importance of the development of more accurate and performing analytical techniques to correctly characterize the chemical composition of the manufactured drugs and their behavior under physiological conditions. |
Author | Abel, Ulrich Macis, Marco Ricci, Antonio Guryanov, Ivan Cabri, Walter Ferrazzano, Lucia Tolomelli, Alessandra |
AuthorAffiliation | 1 Department of Chemistry “Giacomo Ciamician”, Alma Mater Studiorum University of Bologna Bologna Italy 2 Fresenius Kabi iPSUM Srl Villadose (RO) Italy 4 Fresenius Kabi Deutschland GmbH Bad Homburg Germany 3 Institute of Chemistry St. Petersburg State University St. Petersburg Russia |
AuthorAffiliation_xml | – name: 2 Fresenius Kabi iPSUM Srl Villadose (RO) Italy – name: 4 Fresenius Kabi Deutschland GmbH Bad Homburg Germany – name: 3 Institute of Chemistry St. Petersburg State University St. Petersburg Russia – name: 1 Department of Chemistry “Giacomo Ciamician”, Alma Mater Studiorum University of Bologna Bologna Italy |
Author_xml | – sequence: 1 givenname: Lucia surname: Ferrazzano fullname: Ferrazzano, Lucia organization: University of Bologna – sequence: 2 givenname: Alessandra surname: Tolomelli fullname: Tolomelli, Alessandra organization: University of Bologna – sequence: 3 givenname: Ivan orcidid: 0000-0001-6897-3528 surname: Guryanov fullname: Guryanov, Ivan email: ivan.guryanov1@gmail.com organization: St. Petersburg State University – sequence: 4 givenname: Marco surname: Macis fullname: Macis, Marco organization: Fresenius Kabi iPSUM Srl – sequence: 5 givenname: Ulrich surname: Abel fullname: Abel, Ulrich organization: Fresenius Kabi Deutschland GmbH – sequence: 6 givenname: Antonio surname: Ricci fullname: Ricci, Antonio email: antonio.ricci@fresenius‐kabi.com organization: Fresenius Kabi iPSUM Srl – sequence: 7 givenname: Walter surname: Cabri fullname: Cabri, Walter organization: Fresenius Kabi iPSUM Srl |
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Cites_doi | 10.1021/jm0003900 10.1007/s40005-016-0284-6 10.1007/s00345-013-1157-5 10.1016/j.jval.2019.04.019 10.1080/14656566.2021.1948012 10.1021/acs.oprd.9b00540 10.1124/jpet.301.1.95 10.1093/bioinformatics/btr284 10.1124/dmd.113.051706 10.3390/ijms221910253 10.1371/journal.pbio.0060017 10.1021/acs.oprd.9b00430 10.1021/jm00101a003 10.2174/1385272825666210610155047 10.1038/d41573-021-00111-w 10.1016/j.clinthera.2009.11.009 10.1016/j.str.2013.10.016 10.1146/annurev.bi.19.070150.002205 10.1021/jm00160a008 10.1124/dmd.111.039883 10.3389/fmolb.2021.697586 10.1517/14656566.5.10.2171 10.1007/s40265-014-0211-y 10.3390/cancers12010051 10.1007/s40005-016-0250-3 10.1016/S0165-022X(00)00143-3 10.1111/j.1399-3011.1988.tb01373.x 10.3389/fchem.2021.682675 |
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Copyright | 2023 The Authors. published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd. 2023 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd. 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. |
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Keywords | dihydroorotate degarelix peptide metabolism hydantoin |
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Snippet | One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by... Abstract One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be... Abstract One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be... |
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SubjectTerms | Amino acids Calibration Cancer therapies Chromatography degarelix dihydroorotate Gonadotropin-Releasing Hormone Hormone Antagonists hydantoin Isomerism Liver metabolism Methods Molecular weight Oligopeptides Original peptide Peptides Pharmaceuticals Pharmacology Prostate cancer Proteins |
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Title | Investigation of the GnRH antagonist degarelix isomerization in biological matrices |
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