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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1509319

Pharmacokinetics, Bioavailability, and Tissue Distribution of MRTX1133 in Rats Using UHPLC-MS/MS

Provisionally accepted
Wei Lu Wei Lu 1Qibin Wang Qibin Wang 1Yuan Zhou Yuan Zhou 1Huijuan Tang Huijuan Tang 2Wanying Shen Wanying Shen 2Yijun Tang Yijun Tang 1Pan Lei Pan Lei 1*
  • 1 Taihe Hospital, Hubei University of Medicine, Shiyan, China
  • 2 Huazhong Agricultural University, Wuhan, Hubei Province, China

The final, formatted version of the article will be published soon.

    MRTX1133 is a selective and reversible small molecule inhibitor of KRAS (G12D), which significantly delays the progression of solid tumors. However, no study is available on the absorption, distribution, and excretion of MRTX1133. This study described a fast ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry (UHPLC-MS/MS) method for the determination of MRTX1133 in rat plasma, liver, kidney, lung, spleen, heart, pancreas, and intestine homogenate, and urine. The calibration curve for MRTX1133 in plasma and other homogenates was linear, with r 2 > 0.99. The intra-and interday accuracies were ranged from 85% to 115% and precision were within ± 10%. The matrix effect and recovery were within ± 15 %. The validated method was applied to the pharmacokinetics, bioavailability, tissue distribution, and excretion of MRTX1133 after oral administration (25 mg/kg) and the intravenous administration (5 mg•kg -1 ). The results showed that MRTX1133 was quickly absorbed, while the C max was 129.90 ± 25.23 ng•mL -1 in the plasma at 45 min after oral administration. The plasma half-life time (t1/2) of MRTX1133 was 1.12 ± 0.46 h after oral administration and 2.88 ± 1.08 h after intravenous administration.The bioavailability of MRTX1133 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 hours. The excretion ratio of prototype MRTX1133 through kidney was 22.59 % ± 3.22 % after 24 h. This study provided a reference for the quantitative determination of MTRX1133 in preclinical or clinical trials

    Keywords: MRTX1133, UHPLC-MS/MS, pharmacokinetics, distribution, excretion

    Received: 10 Oct 2024; Accepted: 29 Nov 2024.

    Copyright: © 2024 Lu, Wang, Zhou, Tang, Shen, Tang and Lei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Pan Lei, Taihe Hospital, Hubei University of Medicine, Shiyan, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.