He Xueru, Li Ying, Li Yajing, Guo Caihui, Fu Yuhao, Xun Xuejiao, Wang Zhi, Dong Zhanjun
Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050051, China; Graduate School, Hebei Medical University, Shijiazhuang 050017, China.
Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050051, China.
Biomed Pharmacother. 2023 Jun;162:114663. doi: 10.1016/j.biopha.2023.114663. Epub 2023 Apr 5.
Donafenib (DONA), a deuterium derivative of sorafenib, is used for advanced hepatocellular carcinoma (HCC). Dapagliflozin (DAPA) and canagliflozin (CANA) are sodium-glucose co-transporter 2 (SGLT2) inhibitors used for T2DM, which is frequently comorbid with HCC. Three drugs are substrates of UGT1A9 isoenzyme. This study aimed to evaluate donafenib-dapagliflozin and donafenib-canagliflozin pharmacokinetic interactions and explore the potential mechanisms. Rats were divided into seven groups (n = 6) that received donafenib (1), dapagliflozin (2), canagliflozin (3), dapagliflozin and donafenib (4), canagliflozin and donafenib (5), donafenib and dapagliflozin (6), donafenib and canagliflozin (7). The concentrations of drugs were determined by an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. The messenger RNA (mRNA) expressions were measured by quantitative RT-PCR. Multiple doses of dapagliflozin caused donafenib maximum plasma concentration (C) to increase 37.01%. Canagliflozin increased donafenib C 1.77-fold and the area under the plasma concentration-time curves (AUC and AUC) 1.39- and 1.41-fold, respectively, while reducing the apparent clearance (CL) 28.38%. Multiple doses of donafenib increased dapagliflozin AUC 1.61-fold, AUC 1.77-fold, whereas its CL reduced 40.50%. Furthermore, donafenib caused similar changes in canagliflozin pharmacokinetics. The PCR results demonstrated that dapagliflozin inhibited the mRNA expression of Ugt1a7 in liver and donafenib decreased the expression of Ugt1a7 mRNA in liver and intestine. Increased exposure to these drugs may be due to their metabolism inhibition mediated by Ugt1a7. These pharmacokinetic interactions observed in this study may be of clinical significance, which may help adjust dose properly and avoid toxicity effects in patients with HCC and T2DM.
多纳非尼（DONA）是索拉非尼的氘代衍生物，用于治疗晚期肝细胞癌（HCC）。达格列净（DAPA）和卡格列净（CANA）是用于2型糖尿病（T2DM）的钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂，T2DM常与HCC合并存在。这三种药物都是UGT1A9同工酶的底物。本研究旨在评估多纳非尼-达格列净和多纳非尼-卡格列净的药代动力学相互作用，并探索其潜在机制。将大鼠分为七组（n = 6），分别给予多纳非尼（1组）、达格列净（2组）、卡格列净（3组）、达格列净和多纳非尼（4组）、卡格列净和多纳非尼（5组）、多纳非尼和达格列净（6组）、多纳非尼和卡格列净（7组）。采用超高效液相色谱-串联质谱（UPLC-MS/MS）法测定药物浓度。通过定量RT-PCR测定信使核糖核酸（mRNA）表达。多次给予达格列净使多纳非尼的最大血浆浓度（Cmax）升高37.01%。卡格列净使多纳非尼的Cmax升高1.77倍，血浆浓度-时间曲线下面积（AUCτ和AUC0-∞）分别升高1.39倍和1.41倍，同时使表观清除率（CL）降低28.38%。多次给予多纳非尼使达格列净的AUCτ升高1.61倍、AUC0-∞升高1.77倍，而其CL降低40.50%。此外，多纳非尼对卡格列净的药代动力学也产生了类似的影响。PCR结果表明，达格列净抑制肝脏中Ugt1a7的mRNA表达，多纳非尼降低肝脏和肠道中Ugt1a7 mRNA的表达。这些药物暴露量的增加可能是由于Ugt1a7介导的代谢抑制作用。本研究中观察到的这些药代动力学相互作用可能具有临床意义，有助于合理调整剂量，避免HCC和T2DM患者出现毒性反应。
