Iwase Mariko, Nishimura Yuki, Kurata Norimitsu, Namba Hokuto, Hirai Takahito, Kiuchi Yuji
Department of Pharmacology, Showa University School of Medicine.
Faculty of Arts and Sciences at Fujiyoshida, Showa University.
Biol Pharm Bull. 2017;40(10):1654-1660. doi: 10.1248/bpb.b17-00118.
OTC drugs have an important role in self-medication. However, the pharmacokinetic properties of some OTC drugs have not been fully investigated and reports concerning their drug interactions are insufficient. Several gastrointestinal drugs are available as OTC drugs. Because of their pharmacological properties, these drugs are often used concomitantly with other drugs. Therefore, it is important to predict the possible drug interactions among these drugs. In the current study, we investigated the inhibitory effects of five gastrointestinal drugs, namely loperamide, oxethazaine, papaverine, pirenzepine, and trimebutine, on CYP activities in human liver microsomes. Furthermore, we calculated the ratio of the intrinsic clearance of each CYP substrate in the presence or absence of the gastrointestinal drugs. The possibility of drug interactions in vivo was predicted by cut-off criteria. CYP3A4 activity was markedly inhibited by trimebutine, papaverine, and oxethazaine. Their inhibitory properties were competitive and the K values were 6.56, 12.8, and 3.08 µM, respectively. Alternative R values of CYP3A4 exceeded the cut-off level. These results suggested that drug interactions mediated by CYP3A4 may occur during treatment with these gastrointestinal drugs, necessitating the confirmation of the clinical significance of these drug interactions to prevent unexpected adverse effects.
非处方药在自我药疗中发挥着重要作用。然而，一些非处方药的药代动力学特性尚未得到充分研究，有关其药物相互作用的报道也不足。有几种胃肠药物作为非处方药可供使用。由于其药理特性，这些药物常与其他药物联合使用。因此，预测这些药物之间可能的药物相互作用很重要。在本研究中，我们研究了五种胃肠药物，即洛哌丁胺、奥昔卡因、罂粟碱、哌仑西平和曲美布汀对人肝微粒体中细胞色素P450（CYP）活性的抑制作用。此外，我们计算了存在或不存在胃肠药物时每种CYP底物的内在清除率比值。通过截断标准预测体内药物相互作用的可能性。曲美布汀、罂粟碱和奥昔卡因显著抑制CYP3A4活性。它们的抑制特性是竞争性的，K值分别为6.56、12.8和3.08µM。CYP3A4的替代R值超过截断水平。这些结果表明，在用这些胃肠药物治疗期间可能发生由CYP3A4介导的药物相互作用，有必要确认这些药物相互作用的临床意义以预防意外的不良反应。
