Comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of mycophenolic acid

Mycophenolate mofetil (MMF) is almost completely absorbed from the gut and is rapidly de-esterified into its active drug, mycophenolic acid (MPA). The main metabolite is glucuronidated MPA (MPAG), which is excreted into bile and undergoes enterohepatic recirculation. Studies in healthy volunteers tr eated with cholestyramine show that interruption of the enterohepatic recir culation decreases MPA exposure by approximately 40%. published data show a difference in mycophenolic acid plasma concentrations between kidney trans plant recipients treated with MMF plus cyclosporine (CsA) and those treated with MMF plus tacrolimus (TRL). However, the interpretation of these data is complicated by interpatient differences in variables that may influence MMF pharmacokinetics (e.g., underlying disease, co-medication, and time sin ce transplantation). To understand the influence of TRL and CsA on MMF phar macokinetics (PK) more completely, the authors eliminated confounding varia bles in clinical studies by performing drug interaction studies in inbred r ats. To achieve a steady state, 3 groups of Lewis rats (n = 8 per group) we re treated once daily with oral CsA (8 mg/kg), TRL (4 mg/kg), or placebo on days 0-6 before all rats began once-daily oral treatment with MMF (20 mg/k g) on day 7. Combined treatment with either MMF + CsA, MMF + TRL, or MMF placebo was continued for 1 week (days 8-14). Thereafter, CsA and TRL treat ments were stopped but MMF treatment was continued on days 14-21. Blood was sampled during the 24 hours subsequent to dosing on day 7 (after the first MMF dose), on day 14 (after multiple MMF doses) and on day 21 (after CsA/T RL washout). Rats in the MMF + TRL group and in the MMF + placebo group sho wed a second peak in the MPA-PK profiles consistent with enterohepatic reci rculation of MPA. The MPA-PK profiles for the MMF + CsA-treated animals did not show a second MPA peak. On Day 14, the mean plasma MPA-AUC(0-24 hours) for the CsA-treated animals was significantly less than MPA exposures for rats in the MMF + TRL- and the MMF + placebo-treated groups. Furthermore, i n contrast to results from other investigators, co-administration of CsA an d MMF significantly increased MPAG-AUC(0-24 hours). Serum creatinines did n ot differ among rats in the three groups. CsA but not TRL decreased MPA pla sma levels and increased MPAG-AUC(0-24 hours). These data suggest that CsA inhibits MPAG excretion into bile and offer an explanation for the well-kno wn increased MPA exposure in organ transplant patients caused by conversion from CsA- to TRL-based immunosuppression.