Na Young-Guk, Byeon Jin-Ju, Huh Hyun Wook, Kim Min-Ki, Shin Young G, Lee Hong-Ki, Cho Cheong-Weon
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 99, Daehak-ro, Yuseong-gu, Daejeon 34134, Korea.
Pharmaceutics. 2019 Jul 20;11(7):354. doi: 10.3390/pharmaceutics11070354.
Tadalafil is a cytochrome P450 (CYP) 3A4 substrate. Because there are few data on drug-drug interactions, it is advisable to take sufficient consideration when co-administering tadalafil with CYP3A4 inducers or inhibitors. This study was conducted to assess the effect of ticagrelor, a CYP3A4 inhibitor, on the pharmacokinetic properties of tadalafil after oral administration to rats. A total of 20 Sprague-Dawley male rats were randomly divided into the non-pretreated group and ticagrelor-pretreated group, and tadalafil was orally administered to each group after pretreatment with or without ticagrelor. Blood samples were collected at predetermined time points after oral administration of tadalafil. As a result, systemic exposure of tadalafil in the ticagrelor-pretreated group was significantly increased compared to the non-pretreated group (1.61-fold), and the clearance of tadalafil in the ticagrelor-pretreated group was significantly reduced than the non-pretreated group (37%). The prediction of the drug profile through the one-compartment model could explain the differences of pharmacokinetic properties of tadalafil in the non-pretreated and ticagrelor-pretreated groups. This study suggests that ticagrelor reduces a CYP3A-mediated tadalafil metabolism and that tadalafil and a combination regimen with tadalafil and ticagrelor requires dose control and specific pharmacotherapy.
他达拉非是细胞色素P450（CYP）3A4的底物。由于关于药物相互作用的数据较少，在他达拉非与CYP3A4诱导剂或抑制剂合用时，建议充分考虑。本研究旨在评估CYP3A4抑制剂替格瑞洛对大鼠口服他达拉非后药代动力学特性的影响。将20只雄性Sprague-Dawley大鼠随机分为未预处理组和替格瑞洛预处理组，在有或没有替格瑞洛预处理后，对每组大鼠口服他达拉非。在口服他达拉非后的预定时间点采集血样。结果显示，与未预处理组相比，替格瑞洛预处理组中他达拉非的全身暴露显著增加（1.61倍），且替格瑞洛预处理组中他达拉非的清除率比未预处理组显著降低（37%）。通过单室模型预测药物特征可以解释未预处理组和替格瑞洛预处理组中他达拉非药代动力学特性的差异。本研究表明，替格瑞洛可降低CYP3A介导的他达拉非代谢，且他达拉非以及他达拉非与替格瑞洛的联合用药方案需要进行剂量控制和特定的药物治疗。
