Drug Disposition in the Lower Gastrointestinal Tract: Targeting and Monitoring

Abstract

The increasing prevalence of colonic diseases calls for a better understanding of the various colonic drug absorption barriers of colon-targeted formulations, and for reliable in vitro tools that accurately predict local drug disposition. In vivo relevant incubation conditions have been shown to better capture the composition of the limited colonic fluid and have resulted in relevant degradation and dissolution kinetics of drugs and formulations. Furthermore, drug hurdles such as efflux transporters and metabolising enzymes, and the presence of mucus and microbiome are slowly integrated into drug stability- and permeation assays. Traditionally, the well characterized Caco-2 cell line and the Ussing chamber technique are used to assess the absorption characteristics of small drug molecules. Recently, various stem cell-derived intestinal systems have emerged, closely mimicking epithelial physiology. Models that can assess microbiome-mediated drug metabolism or enable coculturing of gut microbiome with epithelial cells are also increasingly explored. Here we provide a comprehensive overview of the colonic physiology in relation to drug absorption, and review colon-targeting formulation strategies and in vitro tools to characterize colonic drug disposition.

Keywords: colon drug delivery; colonic drug disposition; colonic physiology; drug absorption; drug metabolising enzymes (DME); intestinal in vitro models; microbiome; microphysiological systems (MPS).

Figure 1

Concentration–time profile of celecoxib in plasma samples (▲) and cecal biopsies (●), collected from healthy volunteers after oral intake of one tablet of Celebrex (200 mg celecoxib) with 240 mL of water under fasted conditions. Adopted with permission from [43], Elsevier, 2020.

Figure 2

Schematic overview of a Caco-2 monolayer on a transwell insert. Adopted from [164], MDPI, 2019.

Figure 3

Schematic view of tissue fixation in the Ussing chamber. After the removal of the muscle layer, fat, and sub-mucosa, the tissue clamp is pushed carefully under the intestinal segment. The mucosal side (m) faces the bottom and the serosal membrane (s) faces the top. Then, the tissue holder is pressed down onto the tissue, fixing the tissue in-between the tissue holder and the tissue clamp. After the removal of overlapping tissue, the tissue holder is mounted into the Ussing chamber (4) by fixing it onto the bars (5). The mucosal side can face the left or the right half of the chamber (here the mucosal side faces the left). 6 = connectors for agar-salt bridges; 7 = connectors for carbogen. Adopted with permission from [185], John Wiley & Sons, 2001.

Figure 4

A representation of the generation of 2D and 3D organoids, and their application. Resection-, post mortem-, and biopsy tissue can be used to acquire crypts or single stem cells, which can then be cultured as organoids following described protocols. The 3D Organoids can be exposed to microbes and drugs by microinjection, while the transwell culture (2D) allows both luminal and basolateral exposure. The possible applications are discussed in the text and depicted in the right panel. Adapted with permission from [198], SAGE Publications, 2017.

Figure 5

Organ-on-a-chip. (A): The central microchannel comprises a flexible porous extracellular matrix (ECM)-coated membrane lined with gut epithelial cells, positioned between two vacuum chambers. (B): Mechanical strain is applied to the gut intestinal monolayers by suction from the vacuum chambers. Adopted with permission from [202], Royal Society of Chemistry, 2001.

Figure 6

RepliGut^® planar growing primary epithelial cells on a biomimetic scaffold. Adopted with permission from [210], Altis Biosystems.

Figure 7

EpiIntestinal full thickness tissue cultured at the air-liquid interface. Adopted with permission from [159], Oxford University Press, 2018.

Figure 8

The 3D small intestinal microtissue engineered utilizing bioprinting of an interstitial layer containing adult human intestinal myofibroblasts followed by adult human intestinal epithelial cells creating a bilayered architecture. Adopted with permission from [3], Elsevier, 2018.

Figure 9

Organ-on-a-chip. Duodenum Intestine-Chip from Emulate, including its top view (left) and vertical section (right) showing: the epithelial (1; blue) and vascular (2; pink) cell culture microchannels populated by intestinal epithelial cells (3) and endothelial cells (4), respectively, and separated by a flexible, porous, ECM-coated polydimethylsiloxane (PDMS) membrane (5). Adopted from [158], eLife, 2020.

Figure 10

Schematic overview of the Netherlands Organization for Applied Scientific Research (TNO) in vitro model of the colon (TIM-2). (a) peristaltic compartments containing fecal matter; (b) pH electrode; (c) alkali pump; (d) dialysis liquid circuit with hollow fibre membrane; (e) level sensor; (f) N₂ gas inlet; (g) sampling port; (h) gas outlet; (i) ‘ileal efflux’ container; (j) temperature sensor. Adopted from [5], SpringerLink, 2015.

Figure 11

Schematic overview of SHIME^®. Adopted from [4], SpringerLink, 2015.

Figure 12

Schematic overview of the implementation of a new second unit modified by incorporating a mucosal compartment (=mucosal SHIME or M-SHIME), which contained 100 mucin-covered microcosms per 500 mL suspension. The general experimental design is composed of several double-jacketed vessels, simulating the stomach, small intestine and three main colonic regions. In this experiment, only the first colon compartment (ascending colon) was used and inoculated with a human fecal microbiome. The first ascending colon unit consisted of the conventional set-up that only harbors luminal microbes (=luminal SHIME or L-SHIME), whereas the second unit is the M-SHIME. Adopted with permission from [226], John Wiley & Sons, 2011.

Figure 13

Schematic overview of the human–microbial crosstalk (HuMiX) model including human epithelial cells and gastrointestinal microbes. Adopted from [6], Springer Nature, 2016.

Figure 14

Representation of the microfluidic intestine-chip with microbiome, under the presence of an oxygen gradient (color scale). The human intestinal epithelium is overlaid with its own mucus layer and complex gut biota and positioned over an extracellular matrix-coated porous membrane (grey). The vascular endothelium is situated below the porous membrane. Adopted with permission from [231], Springer Nature, 2019.