TY - JOUR T1 - Gender-Related Differences in Mycophenolate Mofetil-Induced Gastrointestinal Toxicity in Rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 449 LP - 454 DO - 10.1124/dmd.106.012013 VL - 35 IS - 3 AU - Stephan T. Stern AU - Melanie N. Tallman AU - Kristini K. Miles AU - Joseph K. Ritter AU - Robert E. Dupuis AU - Philip C. Smith Y1 - 2007/03/01 UR - http://dmd.aspetjournals.org/content/35/3/449.abstract N2 - Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is included in current combination immunosuppressive regimens following organ transplant. Treatment with MMF often results in dose-limiting gastrointestinal (GI) side effects. The underlying mechanisms responsible for these side effects are not fully understood, but exposure of the intestinal epithelia to MPA during enterohepatic recycling may be involved. The present study demonstrated that female rats are more susceptible to MMF-induced GI toxicity than male rats. Female Sprague-Dawley rats treated chronically with an oral dose of 50 mg of MPA equivalents/kg/day experienced greater GI toxicity than male rats, as measured by diarrhea grade and weight loss. Intestinal microsomes harvested from the upper jejunum of female rats had approximately 3-fold lower MPA glucuronidation rates compared with male rats. In the remaining areas of the small and large intestine, there was also a trend toward decreased glucuronidation in the female rats. The area under the plasma concentration-time curve (AUC) for MPA following an oral dose of 50 mg of MPA equivalents/kg was roughly similar between genders, whereas the AUC for mycophenolic acid phenolic glucuronide (MPAG) was significantly lower in female rats. Female rats also excreted half of the biliary MPAG as male rats. The greater susceptibility of female rats to MMF-induced gastrointestinal toxicity, despite diminished intestinal MPA exposure via reduced biliary excretion of MPAG, may result from reduced protection of enterocytes by in situ glucuronidation. Likewise, susceptibility to MMF-induced GI toxicity in humans may also result from variable intestinal glucuronidation due to UDP glucuronosyltransferase polymorphisms or differential expression. The American Society for Pharmacology and Experimental Therapeutics ER -