Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania.
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania
Drug Metab Dispos. 2022 Jun;50(6):750-761. doi: 10.1124/dmd.122.000831. Epub 2022 Mar 26.
Intricacies in intestinal physiology, drug properties, and food effects should be incorporated into models to predict complex oral drug absorption. A previously published human continuous intestinal absorption model based on the convection-diffusion equation was modified specifically for the male Sprague-Dawley rat in this report. Species-specific physiologic conditions along intestinal length - experimental velocity and pH under fasted and fed conditions, were measured and incorporated into the intestinal absorption model. Concentration-time (C-t) profiles were measured upon a single intravenous and peroral (PO) dose for three drugs: amlodipine (AML), digoxin (DIG), and glyburide (GLY). Absorption profiles were predicted and compared with experimentally collected data under three feeding conditions: 12-hour fasted rats were provided food at two specific times after oral drug dose (1 hour and 2 hours for AML and GLY; 0.5 hours and 1 hour for DIG), or they were provided food for the entire study. Intravenous versus PO C-t profiles suggested absorption even at later times and informed design of appropriate mathematical input functions based on experimental feeding times. With this model, AML, DIG, and GLY oral C-t profiles for all feeding groups were generally well predicted, with exposure overlap coefficients in the range of 0.80-0.97. Efflux transport for DIG and uptake and efflux transport for GLY were included, modeling uptake transporter inhibition in the presence of food. Results indicate that the continuous intestinal rat model incorporates complex physiologic processes and feeding times relative to drug dose into a simple framework to provide accurate prediction of oral absorption. SIGNIFICANCE STATEMENT: A novel rat continuous intestinal model predicts drug absorption with respect to time and intestinal length. Feeding time relative to dose was modeled as a key effect. Experimental fasted/fed intestinal pH and velocity, efflux and uptake transporter expression along intestinal length, and uptake transporter inhibition in the presence of food were modeled. The model uses the pharmacokinetic profiles of three model drugs and provides a novel framework to study food effects on absorption.
肠道生理学、药物特性和食物效应的复杂性应纳入模型中，以预测复杂的口服药物吸收。本报告专门对之前发表的基于对流扩散方程的人体连续肠道吸收模型进行了修改，使其适用于雄性 Sprague-Dawley 大鼠。在该模型中，测量了沿肠道长度的特定物种生理条件 - 空腹和进食条件下的实验速度和 pH，并将其纳入肠道吸收模型中。在三种药物（氨氯地平（AML）、地高辛（DIG）和格列吡嗪（GLY））单次静脉和口服（PO）给药后测量了浓度-时间（C-t）曲线，并与在三种进食条件下收集的实验数据进行了比较：12 小时禁食的大鼠在 PO 给药后 1 小时和 2 小时（AML 和 GLY）或 0.5 小时和 1 小时（DIG）给予食物，或整个研究期间给予食物。静脉与 PO C-t 曲线提示即使在更晚的时间也有吸收，并且基于实验进食时间设计了适当的数学输入函数。使用该模型，对于所有进食组，AML、DIG 和 GLY 的口服 C-t 曲线通常都得到了很好的预测，暴露重叠系数在 0.80-0.97 范围内。DIG 的外排转运和 GLY 的摄取和外排转运被包括在内，以模拟食物存在时摄取转运体的抑制。结果表明，连续肠道大鼠模型将复杂的生理过程和相对于药物剂量的进食时间纳入一个简单的框架中，以提供口服吸收的准确预测。 意义陈述：一种新型大鼠连续肠道模型可预测药物吸收与时间和肠道长度的关系。相对于剂量的进食时间被建模为关键影响因素。实验性空腹/进食肠道 pH 和速度、沿肠道长度的外排和摄取转运体表达以及食物存在时摄取转运体的抑制均被建模。该模型使用三种模型药物的药代动力学曲线，为研究食物对吸收的影响提供了一个新的框架。
