Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (S.A., A.Y., S.H., H.S., A.H.); DMPK Research Department, Teijin Pharma Limited, Tokyo, Japan (S.A.); Chromosome Engineering Research Center (Y.K.) and Division of Genome and Cellular Functions, Department of Molecular and Cellular Biology, School of Life Science, Faculty of Medicine (Y.K.), Tottori University, Tottori, Japan.
Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (S.A., A.Y., S.H., H.S., A.H.); DMPK Research Department, Teijin Pharma Limited, Tokyo, Japan (S.A.); Chromosome Engineering Research Center (Y.K.) and Division of Genome and Cellular Functions, Department of Molecular and Cellular Biology, School of Life Science, Faculty of Medicine (Y.K.), Tottori University, Tottori, Japan
Drug Metab Dispos. 2021 Jul;49(7):581-591. doi: 10.1124/dmd.121.000361. Epub 2021 May 7.
Precise prediction of drug absorption is key to the success of new drug development and efficacious pharmacotherapy. In this study, we developed a new absorption model, the advanced translocation model (ATOM), by extending our previous model, the translocation model. ATOM reproduces the translocation of a substance in the intestinal lumen using a partial differential equation with variable dispersion and convection terms to describe natural flow and micromixing within the intestine under not only fasted but also fed conditions. In comparison with ATOM, it was suggested that a conventional absorption model, advanced compartmental absorption and transit model, tends to underestimate micromixing in the upper intestine, and it is difficult to adequately describe movements under the fasted and fed conditions. ATOM explains the observed nonlinear absorption of midazolam successfully, with a minimal number of scaling factors. Furthermore, ATOM considers the apical and basolateral membrane permeabilities of enterocytes separately and assumes compartmentation of the lamina propria, including blood vessels, to consider intestinal blood flow appropriately. ATOM estimates changes in the intestinal availability caused by drug interaction associated with inhibition of CYP3A and P-glycoprotein in the intestine. Additionally, ATOM can estimate the drug absorption in the fed state considering delayed intestinal drug flow. Therefore, ATOM is a useful tool for the analysis of local pharmacokinetics in the gastrointestinal tract, especially for the estimation of nonlinear drug absorption, which may involve various interactions with intestinal contents or other drugs. SIGNIFICANCE STATEMENT: The newly developed advanced translocation model precisely explains various movements of intestinal contents under fasted and fed conditions, which cannot be adequately described by the current physiological pharmacokinetic models.
精确预测药物吸收是新药开发和有效药物治疗成功的关键。在这项研究中，我们通过扩展之前的转运模型，开发了一种新的吸收模型，即先进转运模型（ATOM）。ATOM 使用带有变分散项和对流项的偏微分方程来模拟肠道腔内物质的转运，以描述在空腹和进食条件下肠道内的自然流动和微混合。与 ATOM 相比，建议常规吸收模型，即先进的隔室吸收和转运模型，往往低估了上肠道中的微混合，并且难以充分描述空腹和进食条件下的运动。ATOM 成功地用最小数量的比例因子解释了咪达唑仑的观察到的非线性吸收。此外，ATOM 分别考虑肠上皮细胞的顶膜和基底外侧膜通透性，并假设包括血管在内的固有层分隔，以适当考虑肠道血流。ATOM 估计与 CYP3A 和 P-糖蛋白在肠道中的抑制相关的药物相互作用引起的肠道可用性变化。此外，ATOM 可以考虑延迟的肠道药物流动来估计进食状态下的药物吸收。因此，ATOM 是分析胃肠道局部药代动力学的有用工具，特别是用于估计可能涉及与肠道内容物或其他药物相互作用的非线性药物吸收。
新开发的先进转运模型精确解释了空腹和进食条件下肠道内容物的各种运动，这是当前生理药代动力学模型无法充分描述的。
Zotero 插件