Pharmacokinetics, bioavailability, and tissue distribution of MRTX1133 in rats using UHPLC-MS/MS
IntroductionMRTX1133 is a selective and reversible small molecule inhibitor of KRAS (G12D), which significantly delays the progression of solid tumors. However, no study on the absorption, distribution, and excretion of MRTX1133.MethodsA fast ultra-high performance liquid chromatography-tandem quadr...
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Frontiers Media S.A.
2024-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1509319/full |
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| author | Wei Lu Wei Lu Rong Zeng Meng Pan Yuan Zhou Huijuan Tang Wanying Shen Yijun Tang Pan Lei Pan Lei Pan Lei |
| author_facet | Wei Lu Wei Lu Rong Zeng Meng Pan Yuan Zhou Huijuan Tang Wanying Shen Yijun Tang Pan Lei Pan Lei Pan Lei |
| author_sort | Wei Lu |
| collection | DOAJ |
| description | IntroductionMRTX1133 is a selective and reversible small molecule inhibitor of KRAS (G12D), which significantly delays the progression of solid tumors. However, no study on the absorption, distribution, and excretion of MRTX1133.MethodsA fast ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry method was developed for the determination of MRTX1133 in rat plasma, tissue homogenate, and urine. The method applied to the pharmacokinetics, bioavailability, tissue distribution, and excretion of MRTX1133 after oral administration (25 mg/kg) and intravenous administration (5 mg/kg).ResultsThe calibration curve for MRTX1133 in plasma and other homogenates was linear, with r2 > 0.99. The intra- and inter-day accuracies were ranged from 85% to 115% and precision were within ± 10%. The matrix effect and recovery were within ± 15 %. The Cmax of MRTX1133 was 129.90 ± 25.23 ng/mL at 45 min after oral administration. The plasma half-life (t1/2) of MRTX1133 was 1.12 ± 0.46 h after oral administration and 2.88 ± 1.08 after intravenous administration. Its bioavailability was 2.92%. Furthermore, MRTX1133 was widely distributed in all the main organs, including liver, kidney, lung, spleen, heart, pancreas, and intestine. MRTX1133 was still detectable in liver, kidney, lung, spleen, heart, and pancreas after 24 h. The excretion ratio of prototype MRTX1133 through kidney was 22.59% ± 3.22% after 24 h.ConclusionsMRTX1133 was quickly absorbed, and widely distributed in the main organs. This study provided a reference for the quantitative determination of MTRX1133 in preclinical or clinical trials. |
| format | Article |
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| institution | OA Journals |
| issn | 1663-9812 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-e5a6cd78a1f2477b9c22217978656cfd2025-08-20T01:58:08ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-12-011510.3389/fphar.2024.15093191509319Pharmacokinetics, bioavailability, and tissue distribution of MRTX1133 in rats using UHPLC-MS/MSWei Lu0Wei Lu1Rong Zeng2Meng Pan3Yuan Zhou4Huijuan Tang5Wanying Shen6Yijun Tang7Pan Lei8Pan Lei9Pan Lei10Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan, ChinaCollege of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, ChinaDepartment of Health Management, Renmin Hospital of Wuhan University, Wuhan, ChinaDepartment of Cardiovascular Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, ChinaDepartment of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan, ChinaHubei Hongshan Laboratory, College of Biomedicine and Health, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, ChinaHubei Hongshan Laboratory, College of Biomedicine and Health, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, ChinaHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, ChinaDepartment of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan, ChinaHubei Hongshan Laboratory, College of Biomedicine and Health, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, ChinaHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, ChinaIntroductionMRTX1133 is a selective and reversible small molecule inhibitor of KRAS (G12D), which significantly delays the progression of solid tumors. However, no study on the absorption, distribution, and excretion of MRTX1133.MethodsA fast ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry method was developed for the determination of MRTX1133 in rat plasma, tissue homogenate, and urine. The method applied to the pharmacokinetics, bioavailability, tissue distribution, and excretion of MRTX1133 after oral administration (25 mg/kg) and intravenous administration (5 mg/kg).ResultsThe calibration curve for MRTX1133 in plasma and other homogenates was linear, with r2 > 0.99. The intra- and inter-day accuracies were ranged from 85% to 115% and precision were within ± 10%. The matrix effect and recovery were within ± 15 %. The Cmax of MRTX1133 was 129.90 ± 25.23 ng/mL at 45 min after oral administration. The plasma half-life (t1/2) of MRTX1133 was 1.12 ± 0.46 h after oral administration and 2.88 ± 1.08 after intravenous administration. Its bioavailability was 2.92%. Furthermore, MRTX1133 was widely distributed in all the main organs, including liver, kidney, lung, spleen, heart, pancreas, and intestine. MRTX1133 was still detectable in liver, kidney, lung, spleen, heart, and pancreas after 24 h. The excretion ratio of prototype MRTX1133 through kidney was 22.59% ± 3.22% after 24 h.ConclusionsMRTX1133 was quickly absorbed, and widely distributed in the main organs. This study provided a reference for the quantitative determination of MTRX1133 in preclinical or clinical trials.https://www.frontiersin.org/articles/10.3389/fphar.2024.1509319/fullMRTX1133UHPLC-MS/MSpharmacokineticsdistributionexcretion |
| spellingShingle | Wei Lu Wei Lu Rong Zeng Meng Pan Yuan Zhou Huijuan Tang Wanying Shen Yijun Tang Pan Lei Pan Lei Pan Lei Pharmacokinetics, bioavailability, and tissue distribution of MRTX1133 in rats using UHPLC-MS/MS Frontiers in Pharmacology MRTX1133 UHPLC-MS/MS pharmacokinetics distribution excretion |
| title | Pharmacokinetics, bioavailability, and tissue distribution of MRTX1133 in rats using UHPLC-MS/MS |
| title_full | Pharmacokinetics, bioavailability, and tissue distribution of MRTX1133 in rats using UHPLC-MS/MS |
| title_fullStr | Pharmacokinetics, bioavailability, and tissue distribution of MRTX1133 in rats using UHPLC-MS/MS |
| title_full_unstemmed | Pharmacokinetics, bioavailability, and tissue distribution of MRTX1133 in rats using UHPLC-MS/MS |
| title_short | Pharmacokinetics, bioavailability, and tissue distribution of MRTX1133 in rats using UHPLC-MS/MS |
| title_sort | pharmacokinetics bioavailability and tissue distribution of mrtx1133 in rats using uhplc ms ms |
| topic | MRTX1133 UHPLC-MS/MS pharmacokinetics distribution excretion |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1509319/full |
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