目的 探究罗沙司他和恩那度司他对环孢素A大鼠体内药动学特征的影响，并初步探究二者联用导致药动学变化的潜在作用机制，为临床两类药物联合用药的安全性、合理性提供实验依据。方法 将18只雄性SD大鼠随机分为对照组、罗沙司他组和恩那度司他组，分别连续7 d ig给予0.9%氯化钠溶液、罗沙司他(10 mg·kg^-1)、恩那度司他(1 mg·kg^-1)，末次给药后30 min后均ig给予环孢素A(10 mg·kg^-1)。采用高效液相色谱串联质谱法（HPLC-MS/MS）测定大鼠不同时间点环孢素A血药浓度，拟合药时曲线并计算药动学参数；通过实时荧光定量PCR（qRT-PCR）检测大鼠肝脏低氧诱导因子（HIF）-1α、细胞色素P450 3A酶（CYP3A）1/2及小肠P-糖蛋白（P-gp）的m RNA表达水平，采用Western blotting检测肝脏HIF-1α、CYP3A1的蛋白表达水平。结果 药动学方面，与对照组相比，罗沙司他组和恩那度司他组的药-时曲线下面积（AUC）_0～t、AUC_0～∞和峰浓度(C_max)显著升高（P<0.01、0.001），清除率（CL）显著降低（P<0.05），罗沙司他组CL降低54.78%，恩那度司他组CL降低94.78%，达峰时间(t_max)和半衰期(t_1/2)无显著性差异。分子水平方面，与对照组相比，罗沙司他组、恩那度司他组大鼠肝脏HIF-1α m RNA表达无显著差异，蛋白水平显著升高（P<0.05）；肝脏CYP3A1的m RNA和蛋白表达、CYP3A2的m RNA表达均显著降低（P<0.05）；小肠P-gp的m RNA表达无显著改变（P>0.05）。结论 罗沙司他和恩那度司他可显著提高大鼠体内环孢素A的全身暴露量、降低其清除率。该作用可能通过翻译后水平稳定肝脏HIF-1α蛋白，进而下调肝脏CYP3A1/2的表达，抑制环孢素A的肝脏代谢清除实现。临床联用使用罗沙司他/恩那度司他与环孢素A时，需密切监测环孢素A血药浓度并及时调整剂量，减少药物蓄积引发的不良反应，保障用药安全。

Objective To investigate the effects of roxadustat and ennaduostat on the pharmacokinetic characteristics of cyclosporine A in rats and to preliminarily explore the potential mechanism of the pharmacokinetic changes caused by their combination, providing experimental evidence for the safety and rationality of the clinical combination of these two drugs. Methods Eighteen male SD rats were randomly divided into the control group, roxadustat group, and ennaduostat group. They were intragastrically administered 0.9% sodium chloride solution, roxadustat(10 mg·kg^-1), and ennaduostat(1 mg·kg^-1) for 7 consecutive days, respectively. Thirty minutes after the last administration, all groups were ig administered cyclosporine A(10 mg·kg^-1). The blood concentration of cyclosporine A at different time points was determined by high-performance liquid chromatography-tandem mass spectrometry（HPLC-MS/MS）, and the pharmacokinetic parameters were calculated by fitting the drug-time curve. The mRNA expression levels of hypoxia-inducible factor（HIF）-1α, cytochrome P450 3A enzymes（CYP3A） 1/2 in the liver and P-glycoprotein（P-gp） in the small intestine were detected by real-time fluorescence quantitative PCR（qRT-PCR）, and the protein expression levels of HIF-1α and CYP3A1 in the liver were detected by Western blotting. Results In terms of pharmacokinetics, compared with the control group, the area under the drug-time curve（AUC）_0～t、AUC_0～∞, and peak concentration(C_max) were significantly increased in the roxadustat group and the ennaduostat group（P < 0.01, 0.001）, and the clearance rate（CL） was significantly decreased（P < 0.05）. The CL in the roxadustat group decreased by 54.78%, and that in the ennaduostat group decreased by 94.78%. There was no significant difference in the time to peak concentration(t_max) and half-life(t_1/2). At the molecular level, compared with the control group, there was no significant difference in the mRNA expression of HIF-1α in the liver of the roxadustat group and the enadutamide group, but the protein expression was significantly increased（P < 0.05）. The mRNA and protein expression of CYP3A1 and the mRNA expression of CYP3A2 in the liver were significantly decreased（P < 0.05）. There was no significant change in the mRNA expression of P-gp in the small intestine（P > 0.05）. Conclusion Roxadustat and ennaduostat can significantly increase the systemic exposure of cyclosporine A in rats and decrease its clearance rate. This effect may be achieved by stabilizing the protein expression of HIF-1α at the post-translational level in the liver, thereby down-regulating the expression of CYP3A1/2 in the liver and inhibiting the hepatic metabolic clearance of cyclosporine A. When roxadustat/ennaduostat and cyclosporine A are used in combination clinically, the blood concentration of cyclosporine A should be closely monitored and the dose adjusted in a timely manner to reduce adverse reactions caused by drug accumulation and ensure the safety of medication.

R969.1；R969.2

常州市科技计划项目(应用基础研究指导性)(CJ20242020); 江苏省药学会-奥赛康医院药学科研基金资助项目(A202424)