This is the first report quantitatively evaluating the clinical induction of CYP3A in the liver and the intestine.

To evaluate hepatic induction, we collected literature data on endogenous biomarkers of hepatic CYP3A induction which we then used to calculate the fold-induction (inducer-mediated change in biomarker level). Literature data on decreases in the area under the curve (AUC) of alfentanil, a CYP3A substrate, caused by CYP3A inducers were also collected. We used the hepatic intrinsic clearance of alfentanil to calculate the hepatic induction ratio (inducer-mediated change in intrinsic clearance). For intestinal induction, the intestinal bioavailability (F_g) of alfentanil was used to calculate the intestinal induction ratio. We determined in vivo maximum induction (E_max) and the average unbound plasma concentration (C_av,u) required for half the maximum induction (EC₅₀) for inducers using an E_max model analysis.

In our results, fold-induction was comparable to the induction ratio at several inducer concentrations, and almost the maximum induction was achieved by a therapeutic dose. Induction ratios in the intestine were similar to the liver.

Our findings suggest that, by knowing only hepatic induction ratios for common inducers, we can quantitatively predict the decreases in the AUC of substrates by CYP3A induction.

这是第一份定量评估肝脏和肠道中CYP3A临床诱导的报告。

为了评估肝诱导作用，我们收集了有关肝CYP3A诱导作用的内源性生物标志物的文献数据，然后将其用于计算折叠诱导（诱导物介导的生物标志物水平的变化）。还收集了有关由CYP3A诱导剂引起的CYP3A底物alfentanil的曲线下面积减少（AUC）的文献数据。我们使用阿芬太尼的肝固有清除率来计算肝诱导率（诱导剂介导的固有清除率变化）。对于肠诱导，使用阿芬太尼的肠生物利用度（F _g）来计算肠诱导比。我们确定了体内最大诱导（E _max）和平均未结合血浆浓度（C _av，u），以使用E _max模型分析得出诱导剂最大诱导量（EC ₅₀）的一半。

在我们的结果中，倍数诱导与几种诱导剂浓度下的诱导率相当，并且通过治疗剂量几乎达到最大诱导。肠道中的诱导率与肝脏相似。

我们的发现表明，通过仅了解常见诱导剂的肝诱导比率，我们可以定量预测CYP3A诱导的底物AUC的降低。