Cyclosporin A, but Not Tacrolimus, Inhibits the Biliary Excretion of Mycophenolic Acid Glucuronide Possibly Mediated by Multidrug Resistance-Associated Protein 2 in Rats

Abstract

The onset of diarrhea after the administration of mycophenolate mofetil (MMF) is possibly associated with the biliary excretion of its metabolite, mycophenolic acid glucuronide (MPAG). This study was undertaken to clarify the mechanism underlying the biliary excretion of MPAG. Intravenously administered mycophenolic acid (MPA, 5 mg/kg) rapidly disappeared from plasma and was efficiently excreted as MPAG in the bile of Wistar (26% of dose) and Sprague-Dawley rats (21% of dose) over 1 h. On the other hand, in spite of the rapid disappearance of MPA from plasma, the biliary excretion of MPAG was very limited in Eisai hyperbilirubinemic rats (EHBRs), which display mutations in multidrug resistance-associated protein 2 (Mrp2)/canalicular multispecific organic anion transporter, and constituted only 0.5% of dose. Instead, high levels of MPA were noted in the plasma of EHBRs. Intravenous administration of CsA (5 mg/kg) to Wistar rats significantly lowered the biliary excretion of MPAG. However, intravenously administered tacrolimus (0.1 mg/kg) failed to produce such effect. In conclusion, it is suggested that there is an efficient MPAG transport mediated by Mrp2 on the bile canalicular membrane of rat hepatocytes and that the therapeutic range of CsA potentially interferes with Mrp2. However, the therapeutic range of tacrolimus does not inhibit the transporter. Thus, it should be noted that MMF coadministered with tacrolimus instead of CsA might increase the occurrence of diarrhea related to the biliary excretion of MPAG in transplant recipients.

Consensus Report on Therapeutic Drug Monitoring of Mycophenolic Acid in Solid Organ Transplantation

“…(4) How can therapeutic concentrations be achieved in clinical practice? (5) What is the cost-effectiveness to maintain patients within the therapeutic window? In the past few years, large clinical trials and pharmacokinetic studies of renal recipients have provided new insights in this discussion.…”

“…This has been clearly shown for CsA with a 30 to 40% lower dose-normalized MPA exposure (and higher MPAG exposure) in patients who received CsA as compared with patients who received tacrolimus or sirolimus (18). The difference in MPA exposure, depending on the concomitant calcineurin inhibitor (CNI), is explained by a pharmacokinetic interaction of CsA with the main MPA metabolite 7-O-MPA glucuronide (7-O-MPAG) (5). CsA inhibits the multidrug resistance protein 2-mediated transport of 7-O-MPAG into the bile, leading to less enterohepatic circulation of MPA and hence lower exposure (5).…”

“…The difference in MPA exposure, depending on the concomitant calcineurin inhibitor (CNI), is explained by a pharmacokinetic interaction of CsA with the main MPA metabolite 7-O-MPA glucuronide (7-O-MPAG) (5). CsA inhibits the multidrug resistance protein 2-mediated transport of 7-O-MPAG into the bile, leading to less enterohepatic circulation of MPA and hence lower exposure (5). This interaction also suggests that if CsA dosages are tapered, then MPA exposure significantly increases, in both adult and pediatric recipients, and after complete discontinuation of CsA, MPA concentrations may increase by 50 to 100% (6).…”

Therapeutic Drug Monitoring of Mycophenolic Acid

“…MPA is metabolized mostly via the uridine diphosphate glucuronyltransferase (UGT) system. The primary inactive metabolite is the phenolic glucuronide mycophenolic acid glucuronide (MPAG), which is transported from liver cells into bile most likely via the ATP-binding cassette transporter MDR1-related protein 2 (Mrp2) (11). Biliary MPAG then enters the gastrointestinal tract, where, under the catalytic action of glucuronidase that is shed from the intestinal flora, it is hydrolyzed back to MPA, which is then recycled into the bloodstream, the so-called enterohepatic circulation (EHC) pathway ( Figure 1).…”

Mycophenolic acid agents: is enteric coating the answer?

“…This reduces systemic MPA availability by decreasing the enterohepatic recirculation, leading to an elimination of the second MPA plasma concentration peak. [23][24][25][26][27][28][29] Limited data have been reported on MMF and tacrolimus drug interaction. In vitro data showed that tacrolimus may increase MPA plasma concentration due to inhibition of UGT.…”