title: Systemic influence of immunosuppressive drugs on small and large bowel transport and barrier function.
abstract: 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 H(3) -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.
authors.affiliation: Department of General, Visceral, and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Maciej
authors.initials: M
authors.lastname: Malinowski
authors.forename: Peter
authors.initials: P
authors.lastname: Martus
authors.forename: Johan Friso
authors.initials: JF
authors.lastname: Lock
authors.forename: Peter
authors.initials: P
authors.lastname: Neuhaus
authors.forename: Martin
authors.initials: M
authors.lastname: Stockmann
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology; D003967:Diarrhea / Q000139:chemically induced; D000068338:Everolimus; D000068876:Fingolimod Hydrochloride; D005947:Glucose / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects; D007420:Intestine, Large / Q000187:drug effects* / Q000502:physiology; D007421:Intestine, Small / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011409:Propylene Glycols / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016572:Cyclosporine; D000068338:Everolimus; D000068876:Fingolimod Hydrochloride; D009173:Mycophenolic Acid; D005947:Glucose; D013110:Sphingosine; D020123:Sirolimus; D016559:Tacrolimus