Jin Guanqin, Zheng Kewei, Liu Shihuang, Yi Huan, Wei Wei, Xu Congjian, Xiang Xiaoqiang, Kang Yu
Clinical Research Center, Obstetrics & Gynecology Hospital of Fudan University, Shanghai 200433, China.
Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, Shanghai 200433, China.
Pharmaceuticals (Basel). 2025 Jun 19;18(6):927. doi: 10.3390/ph18060927.
The anticancer effects of PI3Kα inhibitors (PI3Ki) are constrained by their hyperglycemic side effects, while the efficacy of conventional hypoglycemic agents, such as insulin, metformin, and SGLT-2 inhibitors, in mitigating PI3Ki-induced hyperglycemia remains suboptimal. Dorzagliatin, a novel glucokinase activator, has been approved in China for the management of hyperglycemia, offering a promising alternative. This study aims to investigate the pharmacokinetic properties and potential mechanisms of drug interactions of dorzagliatin in the regulation of PI3K-induced hyperglycemia. Plasma concentrations of WX390, BYL719, and Dorz in mice were measured using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Pharmacokinetic (PK) parameters and PK/PD models were derived by using Phoenix WinNonlin 8.3.5 software. Blood glucose levels at various time points and tumor volume changes over a four-week period were assessed to explore the interactions when PI3Ki were combined with dorzagliatin. The results indicated that, compared to the Dorz group, the combination groups (Dorz + BYL719, Dorz + WX390) exhibited increases in AUC0→t of dorzagliatin by 41.65% and 20.25%, and in C by 33.48% and 13.32%, respectively. In contrast, co-administration of these PI3Ki with dorzagliatin resulted in minimal increase in their plasma exposure. The combination therapy group (Dorz+BYL719) exhibited superior antitumor efficacy compared to the BYL719 group. : Our findings indicate that the drug-drug interactions (DDIs) between dorzagliatin and multiple PI3Ki (including WX390 and BYL719) may partially account for the enhanced antitumor efficacy observed in the combination therapy group compared to PI3Ki monotherapy. This interaction may be explained by the inhibition of P-glycoprotein (P-gp) and the pharmacological mechanism of dorzagliatin regarding the activation of insulin regulation.
PI3Kα抑制剂（PI3Ki）的抗癌作用受到其高血糖副作用的限制，而传统降糖药物，如胰岛素、二甲双胍和SGLT-2抑制剂，在减轻PI3Ki诱导的高血糖方面的疗效仍不尽人意。新型葡萄糖激酶激活剂多扎格列艾汀已在中国获批用于治疗高血糖，提供了一个有前景的替代方案。本研究旨在探讨多扎格列艾汀在调节PI3K诱导的高血糖中的药代动力学特性和药物相互作用的潜在机制。使用高效液相色谱-串联质谱（LC-MS/MS）分析法测定小鼠体内WX390、BYL719和多扎格列艾汀（Dorz）的血浆浓度。使用Phoenix WinNonlin 8.3.5软件推导药代动力学（PK）参数和PK/PD模型。评估各个时间点的血糖水平和四周内肿瘤体积的变化，以探讨PI3Ki与多扎格列艾汀联合使用时的相互作用。结果表明，与多扎格列艾汀组相比，联合治疗组（多扎格列艾汀+BYL719、多扎格列艾汀+WX390）中多扎格列艾汀的AUC0→t分别增加了41.65%和20.25%，C分别增加了33.48%和13.32%。相反，这些PI3Ki与多扎格列艾汀联合给药导致它们的血浆暴露量增加极少。联合治疗组（多扎格列艾汀+BYL719）与BYL719组相比表现出更强的抗肿瘤疗效。我们的研究结果表明，多扎格列艾汀与多种PI3Ki（包括WX390和BYL719）之间的药物-药物相互作用（DDIs）可能部分解释了联合治疗组与PI3Ki单药治疗相比观察到的增强的抗肿瘤疗效。这种相互作用可能是由于P-糖蛋白（P-gp）的抑制以及多扎格列艾汀激活胰岛素调节的药理机制所致。
