Combination therapy is a common approach for clinical treatment of type 2 diabetes mellitus, especially for patients with poor monotherapy. Meta-analysis suggested that omarigliptin, a long-acting DPP-4 inhibitor, combined with pioglitazone might improve the side effects of pioglitazone. However, little is known about the pharmacokinetic properties after a coadministration. In this study, a rapid and reliable method for the simultaneous determination of the pioglitazone and omarigliptin in rat plasma by UHPLC-MS/MS was established and validated for the first time. An exsil mono C18 column (2.0 × 50 mm, 3 μm) was used to separate the analytes and the column temperature was kept at 30°C. Sitagliptin was selected as the internal standard. 0.02% formic acid aqueous solution (A) and methanol-acetonitrile (B) were used as mobile phases with gradient elution at a flow rate of 0.3 mL/min. The elution procedure was as follows: 20%B (0–0.1 min), 80%B (0.1–0.3 min), 80%B (0.3–2.0 min), and 20%B (2.1–3.0 min). A multiple reaction monitor (MRM) was used under positive ionization mode with electrospray ion source to detect pioglitazone (357.1 ⟶ 134.1), omarigliptin (399.2 ⟶ 153.0), and sitagliptin (408.2 ⟶ 235.0). The linear ranges of pioglitazone and omarigliptin were 5–2000 ng/mL and 10–4000 ng/mL, respectively. Good linear relationships were exhibited in the corresponding linear ranges (r ≥ 0.9944). The bioanalytical method was validated, and the selectivity, linearity, sensitivity, accuracy, precision, stability, recovery, and matrix effect were acceptable. The validated method was then successfully applied to pharmacokinetic study of pioglitazone combined with omarigliptin in rats. Results suggested that the combination of the two drugs had little effect on the pharmacokinetic parameters of each other in rats.

中文翻译：

---

UHPLC-MS/MS同时定量大鼠血浆中吡格列酮和奥马格列汀及其在两种药物合用后药代动力学研究中的应用

联合治疗是临床治疗2型糖尿病的常用方法，尤其是单药治疗效果不佳的患者。荟萃分析表明，奥格列汀（一种长效 DPP-4 抑制剂）联合吡格列酮可能会改善吡格列酮的副作用。然而，对共同给药后的药代动力学特性知之甚少。本研究首次建立并验证了一种快速、可靠的 UHPLC-MS/MS 同时测定大鼠血浆中吡格列酮和奥格列汀的方法。一根 exsil mono C18 色谱柱（2.0 × 50 mm，3  μm) 用于分离分析物，柱温保持在 30°C。选择西格列汀作为内标。0.02% 甲酸水溶液 (A) 和甲醇-乙腈 (B) 用作流动相，梯度洗脱，流速为 0.3 mL/min。洗脱程序如下：20%B（0-0.1 分钟）、80%B（0.1-0.3 分钟）、80%B（0.3-2.0 分钟）和 20%B（2.1-3.0 分钟）。在正电离模式下使用多反应监测器 (MRM) 和电喷雾离子源检测吡格列酮 (357.1 ⟶ 134.1)、奥格列汀 (399.2 ⟶ 153.0) 和西格列汀 (408.2 ⟶ 235.0)。吡格列酮和奥格列汀的线性范围分别为 5–2000 ng/mL 和 10–4000 ng/mL。在相应的线性范围内表现出良好的线性关系（r ≥ 0.9944）。生物分析方法经验证，选择性、线性、灵敏度、准确度、精密度、稳定性、回收率和基质效应均可接受。验证后的方法成功应用于吡格列酮联合奥格列汀在大鼠体内的药代动力学研究。结果表明，两种药物联用对彼此在大鼠体内的药代动力学参数影响不大。