Gender-Related Differences in Mycophenolate Mofetil-Induced Gastrointestinal Toxicity in Rats

Abstract

ABSTRACT: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.

Mechanism of Gender-Divergent UDP-Glucuronosyltransferase mRNA Expression in Mouse Liver and Kidney

“…Many drugs that are primarily glucuronidated show gender-divergent clearance, such as S-oxazepam (M Ͼ F) and fenofibrate (F Ͼ M) (Liu et al, 1991;Court et al, 2004). In rodents, there are examples of gender-divergent glucuronidation of drugs and exogenous chemicals, including MPA and BPA (Takeuchi et al, 2004;Stern et al, 2007). Gender differences in drug conjugation are probably linked to gender-divergent expression of drug-metabolizing enzymes.…”

“…In rodents, particularly rats, several other chemicals exhibit gender differences in glucuronidation. Mycophenolic acid (MPA) area under the curve (AUC) is similar between sexes; however, MPA-glucuronide AUC is lower in female rats, suggesting gender differences in glucuronidation rates of MPA (Stern et al, 2007). In addition, bisphenol A (BPA) glucuronidation in female rat liver microsomes is higher than in male counterparts.…”

Androgen Regulation of Renal Uridine Diphosphoglucuronosyltransferase 1A1 in Rats: Fig. 1.

“…For example, transcription of UGT1A1 and 1A6 mRNA in rat Sertoli cells is up-regulated in response to testosterone treatment (Magnanti et al, 2000). Additionally, there are many examples of sex differences in rat glucuronidation, such as for mycophenolic acid glucuronidation in vivo (Stern et al, 2007), phenol red glucuronidation in vivo (Hart et al, 1969), p-nitrophenol glucuronidation in vivo and in renal microsomes (Rush et al, 1983), and 17␤-estradiol in hepatic microsomes (Rao et al, 1977). In some cases these sex differences may be due to factors other than UGT isoform transcription, such as differences in post-translational UGT modification, substrate absorption, cosubstrate abundance, competing metabolic pathways, or metabolite excretion.…”

“…1B); males had higher UGT1A1 and UGT1A common region reactive protein (1ACR) expression, females had slightly higher UGT1A7 expression, and expression of UGT1A6 was comparable between the sexes. Despite these differences in UGT protein expression, renal microsomes from male and female Sprague-Dawley rats have been shown previously to have similar mycophenolate glucuronidation activities (1.6 versus 1.3 nmol/min/mg for male and females, respectively) (Stern et al, 2007). This lack of gender differences in mycophenolate glucuronidation activity may be attributable to offsetting changes in two or more UGTs able to catalyze mycophenolic acid glucuronidation, e.g., females have higher renal microsomal UGT1A7 but lower UGT1A1 levels.…”

Focused DNA microarray analysis for sex-dependent gene expression of drug metabolizing enzymes, transporters and nuclear receptors in rat livers and kidneys

“…Sex-related differences in the toxic susceptibility of rats have been documented for industrial chemicals (Muraoka and Itoh, 1980), environmental pollutants (Knuckles et al, 2004), insecticides (Carlson and DuBois, 1970;Agarwal et al, 1982) and pharmaceuticals (McGovren et al, 1981;Coleman et al, 1990;Wang et al, 2001;Stern et al, 2007). The susceptibility of male rats to acetaminophen-induced hepatotoxicity is higher than that of female rats (Raheja et al, 1983).…”