Comparison of the Effects of Tacrolimus and Cyclosporine on the Pharmacokinetics of Mycophenolic Acid

Abstract

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 treated with cholestyramine show that interruption of the enterohepatic recirculation decreases MPA exposure by approximately 40%. Published data show a difference in mycophenolic acid plasma concentrations between kidney transplant 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 since transplantation). To understand the influence of TRL and CsA on MMF pharmacokinetics (PK) more completely, the authors eliminated confounding variables in clinical studies by performing drug interaction studies in inbred rats. To achieve a steady state, 3 groups of Lewis rats (n = 8 per group) were 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/kg) 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 treatments 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/TRL washout). Rats in the MMF + TRL group and in the MMF + placebo group showed a second peak in the MPA-PK profiles consistent with enterohepatic recirculation 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, in contrast to results from other investigators, co-administration of CsA and MMF significantly increased MPAG-AUC(0-24 hours). Serum creatinines did not differ among rats in the three groups. CsA but not TRL decreased MPA plasma 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-known increased MPA exposure in organ transplant patients caused by conversion from CsA- to TRL-based immunosuppression.

Mycophenolic acid pharmacokinetics in pediatric liver transplant recipients

“…23 Two possibilities have been suggested to underlie these drug interactions: (1) Tac augments the bioavailability of MMF through inhibition of MPA glucuronidation, the primary metabolic pathway for MPA 26 ; and (2) CsA inhibits enterohepatic recycling of MPA. 27 Our additional studies on the pharmacokinetics of mycophenolate glucuronide suggest both these mechanisms may apply and are reported elsewhere. 28 These drug interactions have definite implications for patients because conversion from comedication with CsA to Tac could result in a sudden increase in MPA levels and potential toxicity.…”

MTX or mycophenolate mofetil with CsA as GVHD prophylaxis after reduced-intensity conditioning PBSCT from HLA-identical siblings

“…We selected higher doses of MMF in view of several publications that showed that MMF had lower mycophenolic acid concentration levels when combined with CsA. 11,27 Recent findings from animal model studies have also supported the suggestion that mycophenolic acid levels were lower in allo-HSCT than in solid-organ transplantation. 28 Furthermore, pharmacokinetic assays of mycophenolic acid have shown a higher therapeutic area under the curve at a dosage of 3 g daily in unrelated donor allo-RIC.…”

Effects of gastric emptying on oral mycophenolic acid pharmacokinetics in stable renal allograft recipients

“…Plasma MPA concentrations are influenced by renal graft function [4][5][6], serum albumin binding and concentration [6,7], liver function [4,8] and haemoglobin concentrations [6]. MPA is also subject to pharmacokinetic drug interactions with calcineurin inhibitors and mTOR inhibitors [9][10][11]. Other drugs can also influence the pharmacokinetics of MPA through interaction with the UDP-glucuronosyltransferases (UGTs) or the organic anion transporter MRP2 [1,[12][13][14].…”