{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T08:53:58Z","timestamp":1785315238075,"version":"3.55.0"},"reference-count":17,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T00:00:00Z","timestamp":1734566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>MRTX1133 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A 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\u00a0mg\/kg) and intravenous administration (5\u00a0mg\/kg).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The calibration curve for MRTX1133 in plasma and other homogenates was linear, with <jats:italic>r<\/jats:italic><jats:sup>2<\/jats:sup> &amp;gt; 0.99. The intra- and inter-day accuracies were ranged from 85% to 115% and precision were within \u00b1 10%. The matrix effect and recovery were within \u00b1 15 %. The Cmax of MRTX1133 was 129.90 \u00b1 25.23\u00a0ng\/mL at 45\u00a0min after oral administration. The plasma half-life (t<jats:sub>1\/2<\/jats:sub>) of MRTX1133 was 1.12 \u00b1 0.46 h after oral administration and 2.88 \u00b1 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\u00a0h. The excretion ratio of prototype MRTX1133 through kidney was 22.59% \u00b1 3.22% after 24\u00a0h.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>MRTX1133 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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1509319","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T05:10:23Z","timestamp":1734585023000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Pharmacokinetics, bioavailability, and tissue distribution of MRTX1133 in rats using UHPLC-MS\/MS"],"prefix":"10.3389","volume":"15","author":[{"given":"Wei","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijuan","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanying","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijun","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,12,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1073\/pnas.0903907107","article-title":"Ras membrane orientation and nanodomain localization generate isoform diversity","volume":"107","author":"Abankwa","year":"2010","journal-title":"Proc. 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Oncol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1158\/2159-8290.CD-19-1167","article-title":"The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients","volume":"10","author":"Hallin","year":"2020","journal-title":"Cancer Discov."},{"key":"B6","doi-asserted-by":"publisher","first-page":"4341","DOI":"10.21873\/anticanres.16629","article-title":"Cetuximab enhances the efficacy of MRTX1133, a novel KRASG12D inhibitor, in colorectal cancer treatment","volume":"43","author":"Kataoka","year":"2023","journal-title":"Anticancer Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1016\/j.apsb.2019.03.002","article-title":"Targeting the untargetable KRAS in cancer therapy","volume":"9","author":"Liu","year":"2019","journal-title":"Acta Pharm. Sin. 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Oncol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1016\/j.annonc.2021.06.001","article-title":"Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches","volume":"32","author":"Reck","year":"2021","journal-title":"Ann. Oncol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1038\/s41571-018-0105-0","article-title":"Therapeutic strategies to target RAS-mutant cancers","volume":"15","author":"Ryan","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.cell.2017.06.009","article-title":"RAS proteins and their regulators in human disease","volume":"170","author":"Simanshu","year":"2017","journal-title":"Cell"},{"key":"B14","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/s12943-021-01422-7","article-title":"Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges","volume":"20","author":"Tang","year":"2021","journal-title":"Mol. Cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1146\/annurev-med-080819-033145","article-title":"Therapeutics targeting mutant KRAS","volume":"72","author":"Thein","year":"2021","journal-title":"Annu. Rev. Med."},{"key":"B16","unstructured":"Bioanalytical method validation guidance for industry. Office of medical products and tobacco, center for drug evaluation and ResearchOffice of foods and veterinary medicine, center for veterinary medicine\n          \n          \n          2018"},{"key":"B17","doi-asserted-by":"publisher","first-page":"3123","DOI":"10.1021\/acs.jmedchem.1c01688","article-title":"Identification of MRTX1133, a noncovalent, potent, and selective KRASG12D inhibitor","volume":"65","author":"Wang","year":"2022","journal-title":"J. Med. Chem."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1509319\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T05:10:26Z","timestamp":1734585026000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1509319\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,19]]},"references-count":17,"alternative-id":["10.3389\/fphar.2024.1509319"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1509319","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,19]]},"article-number":"1509319"}}