Noninfectious gastrointestinal (GI) complications of mycophenolic acid therapy: a consequence of local GI toxicity?
Mycophenolic acid (MPA), a reversible inhibitor of inosine 5''-monophosphate dehydrogenase (IMPDH), selectively inhibits T- and B-cell proliferation. MPA exposure correlates inversely with the risk of acute rejection. Mycophenolate mofetil (CellCept; MMF) is an immediate-release formulation of MPA that is absorbed in the stomach and small intestine. Enteric-coated mycophenolate sodium (myfortic; EC-MPS) delays MPA release until the small intestine. There are some indications that EC-MPS may be associated with improved gastrointestinal (GI) toxicity. It is widely believed that systemic MPA exposure determines the extent of GI toxicity. However, intestinal cells absorb purines locally from the gut lumen via passive diffusion and a specific transport mechanism. It seems likely that local, rather than systemic, MPA exposure is responsible for GI events. Acyl-MPAG, a toxic metabolite of MPA, may be produced by GI cells contributing to MPA-related gut toxicity, suggesting that measures to alter the rate or location of MPA absorption could be beneficial. Lastly, the release of N-(2-hydroxyethyl)morpholine following deestification of MMF may have local irritative effects on gastric mucosal cells. Research which more closely focuses on the local gut pathobiology of MPA-containing drugs may provide a much clearer understanding of the dose-limiting toxicity of this drug class.
Arns
W
W
Cologne General Hospital, Merheim Medical Center, Cologne, Germany. wolfgang.arns@uni-koeln.de
D001711:Biotransformation; D065095:Calcineurin Inhibitors; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000145:classification; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects; D016030:Kidney Transplantation / Q000276:immunology*; D009173:Mycophenolic Acid / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid