Human jejunal permeability (P_eff) is determined in the intestinal region with the highest expression of carrier proteins and largest surface area. Intestinal P_eff are often based on multiple parallel transport processes. Site-specific jejunal P_eff cannot reflect the permeability along the intestinal tract, but they are useful for approximating the fraction oral dose absorbed. It seems like drugs with a jejunal P_eff > 1.5 x 10^–4 cm s^–1 will be completely absorbed no matter which transport mechanism(s) are utilized. Many drugs that are significantly effluxed in vitro have a rapid and complete intestinal absorption (i.e. >85%) mediated by passive transcellular diffusion. The determined jejunal P_eff for drugs transported mainly by absorptive carriers (such as peptide and amino acid transporters) will accurately predict the fraction of the dose absorbed as a consequence of the regional expression. The data also show that: (1) the human intestinal epithelium has a large resistance towards large and hydrophilic compounds; and (2) the paracellular route has a low contribution for compounds larger than approximately molecular weight 200. There is a need for more exploratory in vivo studies to clarify drug absorption and first-pass extraction along the intestine. One is encouraged to develop in vivo perfusion techniques for more distal parts of the gastrointestinal tract in humans. This would stimulate the development of more relevant and complex in vitro absorption models and form the basis for an accurate physiologically based pharmacokinetic modelling of oral drug absorption.

The main objective of this review is to discuss recent advancements in the overall investigation and in vivo prediction of drug absorption. The intestinal permeability of an orally administered drug (given the value P_eff) has been widely used to determine the rate and extent of the drug’s intestinal absorption (F_abs) in humans. Preclinical gastrointestinal (GI) absorption models are currently in demand for the pharmaceutical development of novel dosage forms and new drug products. However, there is a strong need to improve our understanding of the interplay between pharmaceutical, biopharmaceutical, biochemical, and physiological factors when predicting F_abs and bioavailability. Currently, our knowledge of GI secretion, GI motility, and regional intestinal permeability, in both healthy subjects and patients with GI diseases, is limited by the relative inaccessibility of some intestinal segments of the human GI tract. In particular, our understanding of the complex and highly dynamic physiology of the region from the mid-jejunum to the sigmoid colon could be significantly improved. One approach to the assessment of intestinal permeability is to use animal models that allow these intestinal regions to be investigated in detail and then to compare the results with those from simple human permeability models such as cell cultures. Investigation of intestinal drug permeation processes is a crucial biopharmaceutical step in the development of oral pharmaceutical products. The determination of the intestinal P_eff for a specific drug is dependent on the technique, model, and conditions applied, and is influenced by multiple interactions between the drug molecule and the biological membranes.

The gastrointestinal tract is particularly vulnerable to off-target effects of antineoplastic drugs because intestinal epithelial cells proliferate rapidly and have a complex immunological interaction with gut microbiota. As a result, up to 40–100% of all cancer patients dosed with chemotherapeutics experience gut toxicity, called chemotherapeutics-induced intestinal mucositis (CIM). The condition is associated with histological changes and inflammation in the mucosa arising from stem-cell apoptosis and disturbed cellular renewal and maturation processes. In turn, this results in various pathologies, including ulceration, pain, nausea, diarrhea, and bacterial translocation sepsis. In addition to reducing patient quality-of-life, CIM often leads to dose-reduction and subsequent decrease of anticancer effect. Despite decades of experimental and clinical investigations CIM remains an unsolved clinical issue, and there is a strong consensus that effective strategies are needed for preventing and treating CIM. Recent progress in the understanding of the molecular and functional pathology of CIM had provided many new potential targets and opportunities for treatment. This review presents an overview of the functions and physiology of the healthy intestinal barrier followed by a summary of the pathophysiological mechanisms involved in the development of CIM. Finally, we highlight some pharmacological and microbial interventions that have shown potential. Conclusively, one must accept that to date no single treatment has substantially transformed the clinical management of CIM. We therefore believe that the best chance for success is to use combination treatments. An optimal combination treatment will likely include prophylactics (e.g., antibiotics/probiotics) and drugs that impact the acute phase (e.g., anti-oxidants, apoptosis inhibitors, and anti-inflammatory agents) as well as the recovery phase (e.g., stimulation of proliferation and adaptation).