Yan Qing, Xu Xiaolan, Ran Xiaohua, Bai Chenxia, Jiang Qikun, Zhang Tianhong
Department of Pharmaceutical Analysis, Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
Department of Pharmaceutical Analysis, Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
J Chromatogr B Analyt Technol Biomed Life Sci. 2025 Feb 1;1252:124436. doi: 10.1016/j.jchromb.2024.124436. Epub 2024 Dec 28.
Gemcitabine (GEM) has been extensively applied in treating various solid tumors. Nonetheless, GEM is easily metabolized in vivo by cytidine deaminase (CDA) to inactive 2', 2'-Difluorodeoxyuridine (dFdU) results in a low oral bioavailability, which limit its clinical application. It was found that Cedazuridine (CDZ) could effectively inhibit the deamination of the drug by CDA, and its combination with GEM might affect the oral bioavailability of GEM. To investigate the effect of CDZ on the bioavailability and metabolism of GEM after oral administration, an HPLC-MS/MS method was developed for the simultaneous determination of CDZ, GEM, and its metabolite dFdU in mouse plasma. The separation of CDZ, GEM and dFdU was performed on an acetonitrile and water containing 0.1 % formic acid in isocratic elution on a COSMOSIL® 5C18-PAQ packed column (150 × 4.6 mm, 2.6 µm). The three analytes and the internal standard were determined in a multiple reaction monitoring (MRM) mode under positive ion conditions. The three analytes showed good linearity in the range of 5-10,000 ng/mL, and all quality control samples showed good precision and accuracy. The method was successfully applied to the pharmacokinetic study of GEM with CDZ. The results showed that CDZ significantly improved the oral bioavailability of GEM by reducing the metabolism of CDA to GEM in mice, which will provide a reference for the combined application of GEM and CDZ in clinical therapy.
吉西他滨（GEM）已被广泛应用于治疗各种实体瘤。然而，GEM在体内易被胞苷脱氨酶（CDA）代谢为无活性的2'，2'-二氟脱氧尿苷（dFdU），导致口服生物利用度较低，这限制了其临床应用。研究发现，西他唑苷（CDZ）可有效抑制CDA对该药物的脱氨作用，其与GEM联合使用可能会影响GEM的口服生物利用度。为研究CDZ对口服给药后GEM生物利用度和代谢的影响，建立了一种HPLC-MS/MS方法，用于同时测定小鼠血浆中的CDZ、GEM及其代谢产物dFdU。CDZ、GEM和dFdU在COSMOSIL® 5C18-PAQ填充柱（150×4.6 mm，2.6 µm）上，以含0.1%甲酸的乙腈和水进行等度洗脱分离。在正离子条件下，采用多反应监测（MRM）模式测定三种分析物和内标。三种分析物在5-10,000 ng/mL范围内线性良好，所有质量控制样品均显示出良好的精密度和准确度。该方法成功应用于GEM与CDZ的药代动力学研究。结果表明，CDZ通过减少小鼠体内CDA对GEM的代谢，显著提高了GEM的口服生物利用度，这将为GEM与CDZ在临床治疗中的联合应用提供参考。
