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<p>Tirzepatide, a first-in-class dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has been approved for the treatment of type 2 diabetes mellitus and obesity. Despite its remarkable commercial success and expanding global use, validated bioanalytical methods for tirzepatide quantification remain limited. This study aimed to develop and validate a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of tirzepatide in rat plasma and to characterize its pharmacokinetic profile. Plasma samples were prepared by protein precipitation with methanol. Semaglutide, a structurally related GLP-1 analog, was used as the internal standard. Chromatographic separation was achieved using gradient elution with mobile phases consisting of 0.1% formic acid in water and acetonitrile on a C18 column. The lower limit of quantification (LLOQ) of 0.5 ng/mL in rat plasma was achieved. The method was validated according to FDA guidelines. Intra- and inter-day accuracy ranged from 89.32% to 112.01%, and precision was within 9.51% across the concentration range of 0.5 to 1000 ng/mL. Recovery and matrix effects were acceptable, and tirzepatide was stable under various storage and handling conditions. The validated method was applied to pharmacokinetic studies following intravenous (IV, 0.5&#xa0;mg/kg) and subcutaneous (SC, 1 and 2&#xa0;mg/kg) administration in rats. Plasma concentration-time profiles showed multi-exponential decline with dose-proportional pharmacokinetics. The terminal elimination half-life following IV injection was 13.75 ± 1.80&#xa0;h, consistent with the long-acting formulation design. Subcutaneous bioavailability was 61.54–74.92%, indicating efficient absorption from the injection site. This validated LC-MS/MS method provides a quantitative tool for tirzepatide analysis in preclinical pharmacokinetic studies and may support future investigations of this dual incretin agonist.</p>

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A sensitive LC-MS/MS method for tirzepatide in rat plasma with comprehensive pharmacokinetic evaluation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月18日

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  • Sungmin Song,
  • Minju Hyeon,
  • Siyeon Kim,
  • Yeonju Kang,
  • Sehee Hahm,
  • Eunice Bada Park,
  • Beom Soo Shin,
  • Soyoung Shin

摘要

Tirzepatide, a first-in-class dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has been approved for the treatment of type 2 diabetes mellitus and obesity. Despite its remarkable commercial success and expanding global use, validated bioanalytical methods for tirzepatide quantification remain limited. This study aimed to develop and validate a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of tirzepatide in rat plasma and to characterize its pharmacokinetic profile. Plasma samples were prepared by protein precipitation with methanol. Semaglutide, a structurally related GLP-1 analog, was used as the internal standard. Chromatographic separation was achieved using gradient elution with mobile phases consisting of 0.1% formic acid in water and acetonitrile on a C18 column. The lower limit of quantification (LLOQ) of 0.5 ng/mL in rat plasma was achieved. The method was validated according to FDA guidelines. Intra- and inter-day accuracy ranged from 89.32% to 112.01%, and precision was within 9.51% across the concentration range of 0.5 to 1000 ng/mL. Recovery and matrix effects were acceptable, and tirzepatide was stable under various storage and handling conditions. The validated method was applied to pharmacokinetic studies following intravenous (IV, 0.5 mg/kg) and subcutaneous (SC, 1 and 2 mg/kg) administration in rats. Plasma concentration-time profiles showed multi-exponential decline with dose-proportional pharmacokinetics. The terminal elimination half-life following IV injection was 13.75 ± 1.80 h, consistent with the long-acting formulation design. Subcutaneous bioavailability was 61.54–74.92%, indicating efficient absorption from the injection site. This validated LC-MS/MS method provides a quantitative tool for tirzepatide analysis in preclinical pharmacokinetic studies and may support future investigations of this dual incretin agonist.