Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation

Abstract

Background: Steroids have been shown to induce the hepatic glucuronyltransferase (GT) expression enhancing the activity of uridine diphosphate-GT, the enzyme responsible for mycophenolic acid (MPA) metabolism. The impact of steroids on MPA pharmacokinetics, however, has not been investigated to date.

Methods: As a part of a steroid-sparing clinical trial, we studied the effect of steroids on MPA bioavailability in 26 kidney transplant recipients.

Results: Despite that the MMF dose did not change significantly with time, dose-normalized MPA AUC0-12h was lower during the first month (triple therapy, high doses of steroids) than at month 6 post-surgery (triple therapy, low maintenance dose of steroids (32.94 +/- 10.98 vs. 50.87 +/- 22.37 microg/mL. h; P < 0.01). During the steroid tapering and withdrawal phase (from month 6 to 21 post-Tx), plasma MPA trough and peak concentration as well as AUC0-12h progressively increased, while plasma MPA clearance and MPAG (the major MPA metabolite) trough levels declined. Renal function was stable throughout. Since cyclosporine A (CsA) may interfere with MPA pharmacokinetics, MPA and CsA also were measured in an additional control group of 12 kidney transplant patients at month 21 post-Tx who were still on triple therapy (MMF, CsA and steroids). Despite a similar CsA exposure, the control group had a significantly lower MPA AUC0-12h and higher MPAG trough concentration than patients on dual therapy at month 21 post-Tx.

Conclusion: These findings indicate that steroids interfere with MPA bioavailability, and that discontinuation of the drug results in higher MPA exposure, which may compensate at least in part for the lower immunosuppressive level achieved with the remaining dual therapy with CsA and MMF.