Cytochrome P450 (CYP)3A4 induction by drugs and pesticides plays a critical role in the enhancement of pyrrolizidine alkaloid (PA) toxicity as it leads to increased formation of hepatotoxic dehydro-PA metabolites. Addressing the need for a quantitative analysis of this interaction, we developed a physiologically-based toxicokinetic (PBTK) model. Specifically, the model describes the impact of the well-characterized CYP3A4 inducer rifampicin on the kinetics of retrorsine, which is a prototypic PA and contaminant in herbal teas. Based on consumption data, the kinetics after daily intake of retrorsine were simulated with concomitant rifampicin treatment. Strongest impact on retrorsine kinetics (plasma AUC\(_{24}\) and \(C_{{\text {max}}}\) reduced to 67% and 74% compared to the rifampicin-free reference) was predicted directly after withdrawal of rifampicin. At this time point, the competitive inhibitory effect of rifampicin stopped, while CYP3A4 induction was still near its maximum. Due to the impacted metabolism kinetics, the cumulative formation of intestinal retrorsine CYP3A4 metabolites increased to 254% (from 10 to 25 nmol), while the cumulative formation of hepatic CYP3A4 metabolites was not affected (57 nmol). Return to baseline PA toxicokinetics was predicted 14 days after stop of a 14-day rifampicin treatment. In conclusion, the PBTK model showed to be a promising tool to assess the dynamic interplay of enzyme induction and toxification pathways.

药物和农药诱导细胞色素 P450 (CYP)3A4 在增强吡咯里西啶生物碱 (PA) 毒性方面发挥着关键作用，因为它会导致肝毒性脱氢 PA 代谢物的形成增加。为了满足对这种相互作用进行定量分析的需求，我们开发了一种基于生理学的毒代动力学 (PBTK) 模型。具体来说，该模型描述了充分表征的 CYP3A4 诱导剂利福平对逆转录酶动力学的影响，逆转录酶是一种原型 PA 和花草茶中的污染物。根据消耗数据，模拟每日摄入逆托辛并同时进行利福平治疗后的动力学。直接预测对逆转录碱动力学的最大影响（与不含利福平的参考相比，血浆 AUC \(_{24}\)和\(C_{{\text {max}}}\)降低至 67% 和 74%）利福平停药。此时，利福平的竞争性抑制作用停止，而CYP3A4的诱导仍接近其最大值。由于代谢动力学受到影响，肠道逆转录酶 CYP3A4 代谢物的累积形成增加至 254%（从 10 至 25 nmol），而肝脏 CYP3A4 代谢物的累积形成不受影响（57 nmol）。预计在 14 天的利福平治疗停止后 14 天，PA 毒代动力学将恢复到基线。总之，PBTK 模型被证明是评估酶诱导和毒性途径动态相互作用的有前途的工具。