Simultaneous Quantitation of a Novel α1/β1-Blocker TJ0711 and Its Two Metabolites in Dog Plasma Using LC-MS/MS and Its Application to a Pharmacokinetic Study after Intravenous Infusion
TJ0711∙HCl, which is a novel α1/β1 adrenoceptor blocking agent with a ratio of 1:1 for α1/β1, is designed to treat and prevent perioperative hypertension. M1 and M3 were identified as important metabolites in vitro for either antihypertension activity or the maj...
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| Format: | Article |
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MDPI AG
2019-01-01
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| Series: | Pharmaceutics |
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| Online Access: | http://www.mdpi.com/1999-4923/11/1/38 |
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| author | Wenwen Zhu Wanyu Liu Haojv Li Guojia Xu Qian Li Jiangeng Huang Gao Li Luqin Si |
| author_facet | Wenwen Zhu Wanyu Liu Haojv Li Guojia Xu Qian Li Jiangeng Huang Gao Li Luqin Si |
| author_sort | Wenwen Zhu |
| collection | DOAJ |
| description | TJ0711∙HCl, which is a novel α1/β1 adrenoceptor blocking agent with a ratio of 1:1 for α1/β1, is designed to treat and prevent perioperative hypertension. M1 and M3 were identified as important metabolites in vitro for either antihypertension activity or the major metabolite production. In order to obtain a pharmacokinetic profile of both TJ0711 and its metabolites, a rapid, selective, and reliable LC-MS/MS method was developed and validated for simultaneous determination of TJ0711 and two metabolites in beagle dog plasma via efficiently separating two interferential metabolites M16 and M4 from M1 and M3, respectively. Chromatographic separation was achieved on a Waters CORTECS C18+ column (2.1 × 100 mm, 2.7 μm). The mass spectrometric detection was carried out in positive ion MRM mode with ESI+ source. Protein precipitation was used in sample preparation and provided good recovery without a matrix effect. Good linearity was observed at the ranges of 0.5–100 ng/mL for TJ0711 and M3, 0.1–20 ng/mL for M1. Additional validation results were within the acceptance limits followed U.S. FDA guidelines for bioanalytical method validation. This method was successfully applied to an intravenous infusion pharmacokinetic study of TJ0711 at dosing rates of 3, 6, and 12 µg/kg/min in anesthetized beagle dogs for the first time. TJ0711 and its two metabolites exhibited effective proportionality in the dosage of 3 to 12 µg/kg/min. Neither TJ0711 nor its metabolites showed significant differences in pharmacokinetic parameters such as t1/2, CL, and Vss among three dose groups. |
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| id | doaj.art-14e224fdcfb34fc08ac2f03d2fa7c026 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-04-13T06:52:53Z |
| publishDate | 2019-01-01 |
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| series | Pharmaceutics |
| spelling | doaj.art-14e224fdcfb34fc08ac2f03d2fa7c0262022-12-22T02:57:20ZengMDPI AGPharmaceutics1999-49232019-01-011113810.3390/pharmaceutics11010038pharmaceutics11010038Simultaneous Quantitation of a Novel α1/β1-Blocker TJ0711 and Its Two Metabolites in Dog Plasma Using LC-MS/MS and Its Application to a Pharmacokinetic Study after Intravenous InfusionWenwen Zhu0Wanyu Liu1Haojv Li2Guojia Xu3Qian Li4Jiangeng Huang5Gao Li6Luqin Si7School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaSchool of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaSchool of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaSchool of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaSchool of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaSchool of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaSchool of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaSchool of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaTJ0711∙HCl, which is a novel α1/β1 adrenoceptor blocking agent with a ratio of 1:1 for α1/β1, is designed to treat and prevent perioperative hypertension. M1 and M3 were identified as important metabolites in vitro for either antihypertension activity or the major metabolite production. In order to obtain a pharmacokinetic profile of both TJ0711 and its metabolites, a rapid, selective, and reliable LC-MS/MS method was developed and validated for simultaneous determination of TJ0711 and two metabolites in beagle dog plasma via efficiently separating two interferential metabolites M16 and M4 from M1 and M3, respectively. Chromatographic separation was achieved on a Waters CORTECS C18+ column (2.1 × 100 mm, 2.7 μm). The mass spectrometric detection was carried out in positive ion MRM mode with ESI+ source. Protein precipitation was used in sample preparation and provided good recovery without a matrix effect. Good linearity was observed at the ranges of 0.5–100 ng/mL for TJ0711 and M3, 0.1–20 ng/mL for M1. Additional validation results were within the acceptance limits followed U.S. FDA guidelines for bioanalytical method validation. This method was successfully applied to an intravenous infusion pharmacokinetic study of TJ0711 at dosing rates of 3, 6, and 12 µg/kg/min in anesthetized beagle dogs for the first time. TJ0711 and its two metabolites exhibited effective proportionality in the dosage of 3 to 12 µg/kg/min. Neither TJ0711 nor its metabolites showed significant differences in pharmacokinetic parameters such as t1/2, CL, and Vss among three dose groups.http://www.mdpi.com/1999-4923/11/1/38TJ0711LC-MS/MSpharmacokineticsmetabolitebeagle dog |
| spellingShingle | Wenwen Zhu Wanyu Liu Haojv Li Guojia Xu Qian Li Jiangeng Huang Gao Li Luqin Si Simultaneous Quantitation of a Novel α1/β1-Blocker TJ0711 and Its Two Metabolites in Dog Plasma Using LC-MS/MS and Its Application to a Pharmacokinetic Study after Intravenous Infusion Pharmaceutics TJ0711 LC-MS/MS pharmacokinetics metabolite beagle dog |
| title | Simultaneous Quantitation of a Novel α1/β1-Blocker TJ0711 and Its Two Metabolites in Dog Plasma Using LC-MS/MS and Its Application to a Pharmacokinetic Study after Intravenous Infusion |
| title_full | Simultaneous Quantitation of a Novel α1/β1-Blocker TJ0711 and Its Two Metabolites in Dog Plasma Using LC-MS/MS and Its Application to a Pharmacokinetic Study after Intravenous Infusion |
| title_fullStr | Simultaneous Quantitation of a Novel α1/β1-Blocker TJ0711 and Its Two Metabolites in Dog Plasma Using LC-MS/MS and Its Application to a Pharmacokinetic Study after Intravenous Infusion |
| title_full_unstemmed | Simultaneous Quantitation of a Novel α1/β1-Blocker TJ0711 and Its Two Metabolites in Dog Plasma Using LC-MS/MS and Its Application to a Pharmacokinetic Study after Intravenous Infusion |
| title_short | Simultaneous Quantitation of a Novel α1/β1-Blocker TJ0711 and Its Two Metabolites in Dog Plasma Using LC-MS/MS and Its Application to a Pharmacokinetic Study after Intravenous Infusion |
| title_sort | simultaneous quantitation of a novel α1 β1 blocker tj0711 and its two metabolites in dog plasma using lc ms ms and its application to a pharmacokinetic study after intravenous infusion |
| topic | TJ0711 LC-MS/MS pharmacokinetics metabolite beagle dog |
| url | http://www.mdpi.com/1999-4923/11/1/38 |
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