DEHA PBPK model in rats_data

Di(2-ethylhexyl) adipate (DEHA), a widely used plasticizer, is a biocompatible ester that has been considered forpotential application as a pharmaceutical excipient. We developed a physiologically-based pharmacokinetic(PBPK) model for DEHA and its primary metabolite, mono(2-ethylhexyl) adipate (MEHA), using a robust bottom-up modeling strategy in rats. In vitro metabolism studies of the adipates, conducted with homogenates from nine rat organs, indicated that esterase(s) appeared to play significant roles in the instability of both adipates with vascular lipases also potentially contributing to the DEHA metabolism. When extrapolating to in vivoclearance, we accounted for physiologically-based, circulatory topology-driven muti-tissue metabolism. The resulting PBPK model reproduced the rapid initial kinetic phase and resolved critical discrepancies, namely, the atypical metabolite formation fraction of MEHA and the implausible initial volume of DEHA, observed withstandard moment analysis. Following oral administration of DEHA, a distinct and reproducible double-peak phenomenon was observed in the plasma concentration-time profile. Given the highly lipophilic nature of DEHA, lymphatic absorption was explicitly modeled and parameterized using in vivo mesenteric lymph data. The model estimated approximately equal contributions of portal-hepatic and lymphatic pathways to the intestinal absorption of DEHA. The current model successfully predicted the plasma concentration-time profiles of DEHA and MEHA following both intravenous and oral administration, supporting the validity of the model. Collectively, this framework may provide a template that can be extended to predict the pharmacokinetics of lipophilic ester prodrugs or excipients.己二酸二(2-乙基己基)酯（Di(2-ethylhexyl) adipate, DEHA）是一种应用广泛的增塑剂，属于生物相容性酯类，曾被探讨作为药用辅料的潜在应用价值。我们采用稳健的自下而上建模策略，构建了针对DEHA及其主要代谢产物己二酸单(2-乙基己基)酯（mono(2-ethylhexyl) adipate, MEHA）的生理药代动力学（physiologically-based pharmacokinetic, PBPK）模型，实验对象为大鼠。针对该己二酸酯类开展的体外代谢研究采用了9种大鼠器官组织匀浆，结果显示酯酶在两种己二酸酯类的代谢不稳定性中发挥了关键作用，同时血管脂肪酶也可能参与DEHA的代谢过程。在将研究结果外推至体内清除率时，我们纳入了基于生理结构、由循环拓扑驱动的多组织代谢因素。所构建的PBPK模型重现了快速初始动力学时相，并解决了两项关键矛盾：一是标准矩分析中观察到的MEHA非典型代谢物生成分数，二是DEHA不合理的初始分布容积。口服给予DEHA后，血浆浓度-时间曲线呈现出显著且可重复的双峰现象。鉴于DEHA具有高度亲脂性，我们明确建模了淋巴吸收过程，并利用体内肠系膜淋巴数据对相关参数进行了拟合。模型估算显示，门肝通路与淋巴通路对DEHA肠道吸收的贡献大致相当。本模型成功预测了静脉与口服给药后DEHA及MEHA的血浆浓度-时间曲线，验证了模型的有效性。综上，该建模框架可为预测亲脂性酯类前药或药用辅料的药代动力学行为提供可推广的参考范式。