Wilson Aze, Tirona Rommel G, Kim Richard B
*Division of Clinical Pharmacology, Department of Medicine, Western University, London, ON, Canada;†Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada; and‡Department of Physiology & Pharmacology, Western University, London, ON, Canada.
Inflamm Bowel Dis. 2017 May;23(5):804-813. doi: 10.1097/MIB.0000000000001062.
Disease-dependent changes in the activity of drug metabolizing enzymes and transporters, such as Cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), are thought to have a major influence on the disposition of shared substrates. However, little is known regarding the in vivo relevance of these 2 proteins during drug therapy for gastrointestinal diseases. Our aim was to elucidate the activity of CYP3A4 and P-gp in subjects with Crohn's disease (CD) and to evaluate their influence on budesonide pharmacokinetics.
A detailed pharmacokinetic assessment was conducted in 8 individuals diagnosed with CD on stable doses of oral budesonide, a putative shared CYP3A4, and P-gp substrate, where hepatic and intestinal CYP3A4 activity were also assessed using intravenous and oral midazolam. In addition, oral fexofenadine was used as an in vivo probe for P-gp activity.
Budesonide area under the curve was highly variable between subjects but similar to previously reported values in healthy subjects. The hepatic and intestinal extraction ratios for midazolam were 0.11 ± 0.06 and 0.64 ± 0.25, respectively; however, CYP3A4 activity was nearly 5-fold lower in our CD cohort compared with published data among healthy subjects. Multivariate regression revealed that only 25% budesonide clearance could be explained based on midazolam or fexofenadine clearance.
Midazolam and fexofenadine disposition profile did not predict budesonide clearance. However, we observed a marked reduction in vivo CYP3A4 activity among individuals with CD. Therefore, changes in CYP3A4 activity in disease states such as CD may be a heretofore underappreciated determinant of variation in drug responsiveness in CD.
药物代谢酶和转运体（如细胞色素P450（CYP）3A4和P-糖蛋白（P-gp））的活性会因疾病而发生变化，这被认为对共同底物的处置有重大影响。然而，对于这两种蛋白在胃肠道疾病药物治疗期间的体内相关性知之甚少。我们的目的是阐明克罗恩病（CD）患者中CYP3A4和P-gp的活性，并评估它们对布地奈德药代动力学的影响。
对8名诊断为CD且口服布地奈德剂量稳定的个体进行了详细的药代动力学评估，布地奈德是一种公认的CYP3A4和P-gp共同底物，同时使用静脉注射和口服咪达唑仑评估肝脏和肠道CYP3A4的活性。此外，口服非索非那定被用作P-gp活性的体内探针。
布地奈德的曲线下面积在个体之间差异很大，但与先前在健康受试者中报道的值相似。咪达唑仑的肝脏和肠道提取率分别为0.11±0.06和0.64±0.25；然而，与健康受试者的已发表数据相比，我们CD队列中的CYP3A4活性低近5倍。多变量回归显示，基于咪达唑仑或非索非那定清除率仅能解释25%的布地奈德清除率。
咪达唑仑和非索非那定的处置情况不能预测布地奈德的清除率。然而，我们观察到CD患者体内CYP3A4活性明显降低。因此，在CD等疾病状态下CYP3A4活性的变化可能是迄今为止在CD中药物反应性变化的一个未被充分认识的决定因素。
