PT  - JOURNAL ARTICLE
AU  - Casey Radice
AU  - Ken Korzekwa
AU  - Swati Nagar
TI  - <strong>Predicting impact of food and feeding time on oral absorption of drugs with a novel rat continuous intestinal absorption model</strong>
AID  - 10.1124/dmd.122.000831
DP  - 2022 Jan 01
TA  - Drug Metabolism and Disposition
PG  - DMD-AR-2022-000831
4099  - http://dmd.aspetjournals.org/content/early/2022/03/26/dmd.122.000831.short
4100  - http://dmd.aspetjournals.org/content/early/2022/03/26/dmd.122.000831.full
AB  - 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 physiological conditions along intestinal length 'x' - 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 IV and 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-hr fasted rats were provided food at two specific times after oral drug dose (1 hr and 2 hr for AML and GLY, 0.5 hr and 1 hr for DIG), or were provided food for the entire study. IV 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 (EOC) 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 physiological 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.