Systemic influence of immunosuppressive drugs on small and large bowel transport and barrier function

Abstract

Summary Immunosuppressive drug (ISD)‐associated gastrointestinal disorders are a relevant risk factor for graft loss or patient death. The pathomechanisms and the incidence of post‐transplantation diarrhea remain to be fully understood. The aim of this study was to characterize the impact of cyclosporine A, tacrolimus (TAC), mycophenolate mofetil (MMF), enteric coated mycophenolic acid (EC‐MPA), sirolimus, everolimus (EVE) and fingolimod (FTY 720) on small and large bowel transport and barrier function. Functions of the small bowel and distal colon of Wistar rats treated for 14 days with one of the drug were analyzed using Ussing chamber method. In detail, the glucose and sodium absorption, chloride secretion, and barrier function were compared. Bowel functions were investigated by inhibition or activation of the electrogenic epithelial transport, as well as by measuring transepithelial H3‐lactulose flux. TAC altered glucose absorption; EVE glucose absorption, small bowel barrier function and chloride secretion; MMF small bowel barrier function; and EC‐MPA glucose absorption and the small bowel barrier function. Drug effects were partially dose‐dependent. In conclusion, different ISD, such as TAC, EVE, MMF, or EC‐MPA lead to different and specific patterns of pathophysiologic changes of small and large bowel barrier and transport function.

MPA Modulates Tight Junctions' Permeability via Midkine/PI3K Pathway in Caco-2 Cells: A Possible Mechanism of Leak-Flux Diarrhea in Organ Transplanted Patients

“…Clinical data show the occurrence of a significant number of drug-induced diarrhea incidences in liver and kidney organ transplanted patients receiving MPA therapy (Helderman and Goral, 2002; Malinowski et al, 2011; Krones and Hogenauer, 2012). Diarrhea can result in dehydration and discomfort in transplanted patients.…”

Tacrolimus Induces Insulin Resistance and Increases the Glucose Absorption in the Jejunum: A Potential Mechanism of the Diabetogenic Effects

“…Although glucose absorption in the intestines plays a crucial role in glucose homeostasis [ 13 ], it is unknown if intestinal glucose absorption is involved in the diabetogenic effect of TAC. According to a previous study, glucose malabsorption in the jejunum after TAC treatment was observed and the effect was dose-dependent [ 14 ]. Therefore, it is reasonable to hypothesize that intestinal glucose absorption participates in the diabetogenic TAC process.…”

Gastrointestinal disorders after immunosuppression: an experimental model to evaluate the influence of monotherapy on motility parameters

“…The dosages used in rats are higher than those administered in humans because of the different body area‐to‐volume ratio and faster hepatic metabolism (Malinowski et al . ). Therefore, clinically relevant doses of immunosuppressants were selected in our study based on previous data and metabolic differences between rodents and humans (Malinowski et al .…”

“…Therefore, clinically relevant doses of immunosuppressants were selected in our study based on previous data and metabolic differences between rodents and humans (Malinowski et al . ). In addition, the solubility of ionizable drugs or pH‐responsive formulations is significantly influenced by the differences in pH along the GI tract and interspecies differences (Merchant et al .…”

“…Dosages were selected by focusing on clinically relevant dosages and considering that the dosage should be higher in rats than in humans because of a different body area‐to‐volume ratio and faster hepatic metabolism (Malinowski et al . ).…”