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Effects of Voriconazole on the Pharmacokinetics of Vonoprazan in Rats.
Drug Design, Development and Therapy ( IF 4.7 ) Pub Date : 2020-06-04 , DOI: 10.2147/dddt.s255427 Jiquan Shen 1 , Bo Wang 1 , Shuanghu Wang 2, 3 , Feifei Chen 2 , Deru Meng 2 , Hui Jiang 2 , Yunfang Zhou 2 , Peiwu Geng 2 , Quan Zhou 2 , Bin Liu 1
Drug Design, Development and Therapy ( IF 4.7 ) Pub Date : 2020-06-04 , DOI: 10.2147/dddt.s255427 Jiquan Shen 1 , Bo Wang 1 , Shuanghu Wang 2, 3 , Feifei Chen 2 , Deru Meng 2 , Hui Jiang 2 , Yunfang Zhou 2 , Peiwu Geng 2 , Quan Zhou 2 , Bin Liu 1
Affiliation
Purpose: The purpose of this study was to examine the effects of voriconazole on the pharmacokinetics of vonoprazan.
Methods: Fifteen Sprague-Dawley rats were randomly divided into three groups: five rats in each group, including control group, single-dose group (a single dose of 30 mg/kg of voriconazole), and multiple-dose group (multiple doses of 30 mg/(kg•day) per dose of voriconazole). Each group of rats was given an oral dose of 10 mg/kg vonoprazan 30 min after the administration of voriconazole or vehicle. After the oral administration of vonoprazan, 50 μL of blood was collected into 1.5-mL heparinized tubes via the caudal vein. The concentration of vonoprazan in plasma was quantified by ultra-performance liquid chromatography/tandem mass spectrometry. Both in vitro effects of voriconazole on vonoprazan and the mechanism of the observed inhibition were studied in rat liver microsomes.
Results: When orally administered, voriconazole increased the area under the plasma concentration–time curve (AUC), prolonged the elimination half-life (t1/2), and decreased the clearance (CL) of vonoprazan; there was no significant difference between the single-dose and multiple-dose groups. Voriconazole inhibited the metabolism of vonoprazan at an IC50 of 2.93 μM and showed mixed inhibition. The results of the in vivo experiments were consistent with those of the in vitro experiments.
Conclusion: Our findings provide the evidence of drug–drug interactions between voriconazole and vonoprazan that could occur with pre-administration of voriconazole. Thus, clinicians should pay attention to the resulting changes in pharmacokinetic parameters and accordingly, adjust the dose of vonoprazan in clinical settings.
Keywords: cytochrome P450, drug–drug interaction, pharmacokinetic, proton pump inhibitor
中文翻译：
伏立康唑对大鼠沃诺拉赞药代动力学的影响。
目的：本研究的目的是检查伏立康唑对沃诺拉赞药代动力学的影响。
方法：15 只 Sprague-Dawley 大鼠随机分为三组：每组 5 只大鼠，包括对照组、单剂量组（单剂量 30 mg/kg 伏立康唑）和多剂量组（多剂量 30 mg /(kg•day) 每剂伏立康唑)。每组大鼠在给予伏立康唑或赋形剂后30分钟口服10mg/kg的沃诺拉赞。口服沃诺拉赞后，通过尾静脉将 50 μL 血液收集到 1.5 mL 肝素化试管中。通过超高效液相色谱/串联质谱法定量血浆中沃诺拉赞的浓度。在大鼠肝微粒体中研究了伏立康唑对沃诺拉赞的体外作用和观察到的抑制机制。
结果：口服时，伏立康唑增加了血药浓度-时间曲线下面积（AUC），延长了消除半衰期（t 1/2），降低了伏诺拉赞的清除率（CL）；单剂量组和多剂量组之间没有显着差异。Voriconazole 以 2.93 μM 的 IC50 抑制 vonoprazan 的代谢，并显示出混合抑制。体内实验结果与体外实验结果一致。
结论：我们的研究结果提供了伏立康唑和沃诺拉赞之间的药物相互作用的证据，这种相互作用可能发生在伏立康唑的预给药中。因此，临床医生应注意由此产生的药代动力学参数变化，并据此在临床环境中调整沃诺拉赞的剂量。
关键词：细胞色素P450，药物相互作用，药代动力学，质子泵抑制剂
更新日期：2020-06-04
Methods: Fifteen Sprague-Dawley rats were randomly divided into three groups: five rats in each group, including control group, single-dose group (a single dose of 30 mg/kg of voriconazole), and multiple-dose group (multiple doses of 30 mg/(kg•day) per dose of voriconazole). Each group of rats was given an oral dose of 10 mg/kg vonoprazan 30 min after the administration of voriconazole or vehicle. After the oral administration of vonoprazan, 50 μL of blood was collected into 1.5-mL heparinized tubes via the caudal vein. The concentration of vonoprazan in plasma was quantified by ultra-performance liquid chromatography/tandem mass spectrometry. Both in vitro effects of voriconazole on vonoprazan and the mechanism of the observed inhibition were studied in rat liver microsomes.
Results: When orally administered, voriconazole increased the area under the plasma concentration–time curve (AUC), prolonged the elimination half-life (t1/2), and decreased the clearance (CL) of vonoprazan; there was no significant difference between the single-dose and multiple-dose groups. Voriconazole inhibited the metabolism of vonoprazan at an IC50 of 2.93 μM and showed mixed inhibition. The results of the in vivo experiments were consistent with those of the in vitro experiments.
Conclusion: Our findings provide the evidence of drug–drug interactions between voriconazole and vonoprazan that could occur with pre-administration of voriconazole. Thus, clinicians should pay attention to the resulting changes in pharmacokinetic parameters and accordingly, adjust the dose of vonoprazan in clinical settings.
Keywords: cytochrome P450, drug–drug interaction, pharmacokinetic, proton pump inhibitor
中文翻译：
伏立康唑对大鼠沃诺拉赞药代动力学的影响。
目的：本研究的目的是检查伏立康唑对沃诺拉赞药代动力学的影响。
方法：15 只 Sprague-Dawley 大鼠随机分为三组：每组 5 只大鼠，包括对照组、单剂量组（单剂量 30 mg/kg 伏立康唑）和多剂量组（多剂量 30 mg /(kg•day) 每剂伏立康唑)。每组大鼠在给予伏立康唑或赋形剂后30分钟口服10mg/kg的沃诺拉赞。口服沃诺拉赞后，通过尾静脉将 50 μL 血液收集到 1.5 mL 肝素化试管中。通过超高效液相色谱/串联质谱法定量血浆中沃诺拉赞的浓度。在大鼠肝微粒体中研究了伏立康唑对沃诺拉赞的体外作用和观察到的抑制机制。
结果：口服时，伏立康唑增加了血药浓度-时间曲线下面积（AUC），延长了消除半衰期（t 1/2），降低了伏诺拉赞的清除率（CL）；单剂量组和多剂量组之间没有显着差异。Voriconazole 以 2.93 μM 的 IC50 抑制 vonoprazan 的代谢，并显示出混合抑制。体内实验结果与体外实验结果一致。
结论：我们的研究结果提供了伏立康唑和沃诺拉赞之间的药物相互作用的证据，这种相互作用可能发生在伏立康唑的预给药中。因此，临床医生应注意由此产生的药代动力学参数变化，并据此在临床环境中调整沃诺拉赞的剂量。
关键词：细胞色素P450，药物相互作用，药代动力学，质子泵抑制剂
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