Szkutnik-Fiedler Danuta, Karbownik Agnieszka, Otto Filip, Maciejewska Julia, Kuźnik Alicja, Grabowski Tomasz, Wolc Anna, Grześkowiak Edmund, Stanisławiak-Rudowicz Joanna, Szałek Edyta
Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, Rokietnicka 3, 60-806 Poznań, Poland.
Students Scientific Association at the Department of Clinical Pharmacy and Biopharmacy, Faculty of Pharmacy, Poznań University of Medical Sciences, Rokietnicka 3, 60-806 Poznań, Poland.
Pharmaceutics. 2024 Dec 9;16(12):1575. doi: 10.3390/pharmaceutics16121575.
Olaparib (OLA) and regorafenib (REG) are metabolized by the CYP3A4 isoenzyme of cytochrome P450. Both drugs are also substrates and inhibitors of the membrane transporters P-glycoprotein and BCRP. Therefore, the potential concomitant use of OLA and REG may result in clinically relevant drug-drug interactions. Knowledge of the influence of membrane transporters and cytochrome P450 enzymes on the pharmacokinetics of drugs makes it possible to assess their impact on the efficacy and safety of therapy.
The study aimed to evaluate the bilateral pharmacokinetic interactions of OLA and REG and its active metabolites after a single administration in healthy rats.
The study was performed in male Wistar rats (n = 24) randomly divided into three groups: one study group, I (n = 8), received REG with OLA, and two control groups, II (n = 8) and III (n = 8), received REG and OLA, respectively. The concentrations of OLA, REG, REG-N-oxide (M-2), and N-desmethyl-REG-N-oxide (M-5) were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The values of the pharmacokinetic parameters of OLA, REG, M-2, and M-5 were determined by non-compartmental analysis with linear interpolation.
After OLA administration, the pharmacokinetic parameters of REG (AUC, t, and t) increased significantly by 3.38-, 2.66-, and 1.82-fold, respectively. On the other hand, REG elimination parameters, i.e., k and Cl/F, were significantly reduced in the study group by 1.77- and 1.70-fold, respectively. In the study group, C and AUC values were also 7.22- and 8.86-fold higher for M-2 and 16.32- and 17.83-fold higher for M-5, respectively. The Metabolite M-2/Parent and Metabolite M-5/Parent ratios for C and AUC increased by 6.52-, 10.74-, 28-, and 13-fold, respectively. After administration of OLA with REG, the C, AUC, and AUC of OLA increased by 2.0-, 3.4-, and 3.4-fold, respectively, compared to the control group. Meanwhile, Cl/F and Vd/F of OLA were significantly decreased in the presence of REG.
OLA was shown to significantly affect the pharmacokinetics of REG and its active metabolites M-2 and M-5 in rats after co-administration of both drugs. There was also a significant effect of REG on the pharmacokinetics of OLA, which may have clinical relevance. The AUC ratios (study group/control group) were 3.41 and 3.39 for REG and OLA, respectively, indicating that REG and OLA were moderate inhibitors in this preclinical study. The results obtained need to be confirmed in clinical studies. This study may provide guidance on the safety of using both drugs in clinical practice.
奥拉帕利（OLA）和瑞戈非尼（REG）由细胞色素P450的CYP3A4同工酶代谢。这两种药物也是膜转运蛋白P-糖蛋白和乳腺癌耐药蛋白（BCRP）的底物和抑制剂。因此，OLA和REG的潜在联合使用可能导致具有临床意义的药物相互作用。了解膜转运蛋白和细胞色素P450酶对药物药代动力学的影响有助于评估它们对治疗效果和安全性的影响。
本研究旨在评估在健康大鼠单次给药后OLA和REG及其活性代谢产物的双向药代动力学相互作用。
本研究在雄性Wistar大鼠（n = 24）中进行，随机分为三组：一个研究组，I组（n = 8），接受REG与OLA联合给药；两个对照组，II组（n = 8）和III组（n = 8），分别接受REG和OLA。通过超高效液相色谱-串联质谱法（UPLC-MS/MS）测定OLA、REG、REG-N-氧化物（M-2）和N-去甲基-REG-N-氧化物（M-5）的浓度。通过线性内插法的非房室分析确定OLA、REG、M-2和M-5的药代动力学参数值。
给予OLA后，REG的药代动力学参数（AUC、t₁/₂和tmax）分别显著增加3.38倍、2.66倍和1.82倍。另一方面，研究组中REG的消除参数，即k和Cl/F，分别显著降低1.77倍和1.70倍。在研究组中，M-2的Cmax和AUC值分别高出7.22倍和8.86倍，M-5的Cmax和AUC值分别高出16.32倍和17.83倍。Cmax和AUC的代谢物M-2/母体和代谢物M-5/母体比率分别增加了6.52倍、10.74倍、28倍和13倍。与REG联合给予OLA后，与对照组相比，OLA的Cmax、AUC和AUC₀-∞分别增加了2.0倍、3.4倍和3.4倍。同时，在存在REG的情况下，OLA的Cl/F和Vd/F显著降低。
在两种药物联合给药后，OLA被证明对大鼠体内REG及其活性代谢产物M-2和M-5的药代动力学有显著影响。REG对OLA的药代动力学也有显著影响，这可能具有临床相关性。REG和OLA的AUC比率（研究组/对照组）分别为3.41和3.39，表明在这项临床前研究中REG和OLA是中度抑制剂。所得结果需要在临床研究中得到证实。本研究可为临床实践中联合使用这两种药物的安全性提供指导。
