Drug Disposition in the Lower Gastrointestinal Tract: Targeting and Monitoring

Over the past 20–30 years, IBD cases have increased substantially. Similarly, CRC incidence is continuously rising, especially in developing countries, with CRC being the third leading cause of cancer death and the fourth most commonly diagnosed cancer in the world. Considering the need for long-term therapies, drugs with a high colonic exposure but low systemic exposure thereby minimising adverse effects, are most desired for treatment of IBD and CRC. Therefore, different colon-targeted drug delivery systems have been developed and various strategies are currently being used in formulations. To achieve successful colon targeting, several colon-specific hurdles like the luminal contents (low water volume, high viscosity, dynamic stress, variable composition etc.), the presence of a thick mucus lining, an increased barrier tightness compared to the small intestine, and the presence of a metabolically active and patient-specific microbiome need to be addressed and overcome. Currently, in vitro tools fully representing these colon-specific features that can aid in the development of drugs with a favorable profile are limited and, therefore, colon-targeting formulations suffer from inconsistent performance. The successful development of colon-targeting formulations for which efficacy and safety can be guaranteed (despite substantial intra- and interindividual patient differences), requires a thorough understanding of the colon-specific physiology and a tool set that can emulate the colonic environment. However, there has been promising progress in the field. Different models and setups have been developed aiming to mimic GI and colonic physiology and environment, as it is challenging to develop one model representing all in vivo parameters. Media have undergone increments in complexity in order to adequately assess colonic drug behavior in vitro, ranging from simple physiological buffers and more complex biorelevant media to rat cecal contents and human fecal contents that resemble the in vivo situation more closely. With the recent advances made over the past 5–10 years in culturing technologies and in the bioengineering of stem cell-derived systems, the availability of innovative intestinal systems more closely resembling the in vivo environment than traditionally used models like Caco-2 has also increased substantially. Although the characterization with respect to the absorption and metabolism properties of those stem cell-derived, bioengineered platforms and organ chips has been so far mainly focused on the small intestinal regions, it is obvious that the same technologies can be applied for the colon. Despite differences in cell type ratios, tight junctions, water volume, and pH, the most crucial differences between the small and large intestine to be captured with an in vitro tool are the presence of a thick bilayered mucus and commensal bacteria in the colon. Efforts towards a colonic system enabling simultaneous permeability and stability assessments of drugs seem to be on the way or already achieved, but still at low throughput capacity and not characterized for the use in permeability and metabolism studies (Intestine-Chip with microbiome, HuMix).

Table 3 and Table 4 provide an overview of the characteristics of main intestinal in vitro tools discussed here, categorized into epithelial and microbiome platforms. Moreover, when further assessing those novel systems in their capability to accurately capture colonic drug disposition, one should consider the importance of accumulation studies in colonic systems. This is specifically crucial for colon-targeted drugs since they often aim to directly target the epithelium or immune cells of the lamina propria and are actually less desired to enter the blood stream.