In vivo higher glucuronidation of mycophenolic acid in male than in femalerecipients of a cadaveric kidney allograft and under immunosuppressive therapy with mycophenolate mofetil

Mycophenolate mofetil (MMF), an immunosuppressant drug used in organ transp lantation to prevent rejection, is being used increasingly in association w ith cyclosporine and tacrolimus. Mycophenolic acid (MPA) is primarily metab olized in the liver to its 7-O-glucuronide (MPAG) derivative. The concentra tions of MPAG in serum are many times the concentrations of MPA. Although M PAG has not shown immunosuppressant activity, it was postulated that it cou ld displace MPA from its binding sites on albumin and hence increase the bi ologic effects of MPA, This effect could be important for patients with acu te renal failure; under this condition, MPAG was shown to accumulate. The g oal of this study was to document the MPAG/MPA concentration ratio in 100 r enal transplant patients under a mixed immunosuppressive therapy. Further, the study addressed the question of whether MPAG can displace MPA in vivo f rom bound albumin in a representative renal transplant patient population u nder immunosuppressive therapy. Levels of MPAG and MPA were measured by hig h-performance liquid chromatography, The distribution of the ratios was not parametric as it tailed toward elevated values. After a square root transf ormation of the data, parametric analysis was possible. The average MPAG/MP A ratio was 15.0 +/-2.2 for men versus 7.7 +/-0.9 for women. Men treated wi th MMF and tacrolimus showed a lower ratio than patients treated with MMF a nd cyclosporine, confirming that tacrolimus inhibits glucuronidation of MPA . Further, it was determined that at physiologic concentrations, MPAG does not increase the amount of free MPA. Because MPAG can favor the elimination of MPA, it can be concluded that gender differences and cotreatment with t acrolimus must be taken into consideration when MMF is being administered.