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Genvigir et al. J Transl Genet Genom 2020;4:320-55 I http://dx.doi.org/10.20517/jtgg.2020.37 Page 321

Keywords: Immunosuppressive therapy, mycophenolic acid, kidney transplantation, pharmacogenomics,
pharmacodynamics, pharmacokinetics

INTRODUCTION
Mycophenolic acid (MPA) is a potent antiproliferative drug broadly prescribed to prevent acute rejection
in kidney transplantation. MPA is a reversible inhibitor of inosine-5´-monophosphate dehydrogenase
(IMPDH), an important enzyme involved in the de novo synthesis of guanosine nucleotides, which are
[1,2]
essential for the proliferation of T and B cells . Consequently, guanosine nucleotide depletion by MPA
prevents DNA replication, leads to repression of both cell-and humoral-mediated immunity and induces
tolerance to allograft in kidney transplantation [1,3,4] .

IMPDH activity results from the expression of two isoforms, IMPDH type I and type II, which are encoded
[2]
by IMPDH1 and IMPDH2, respectively . Both genes are constitutively expressed in most tissues, though
activated T and B lymphocytes have a higher expression of IMPDH2 . Also, IMPDH type II has a higher
[1]
affinity for MPA compared to IMPDH type I, which makes it a selective and potent antiproliferative drug
[1,3]
for T and B cells [Figure 1].

MPA is available either as an ester prodrug or as a sodium salt, which are equivalent in terms of therapeutic
[5]
effect and MPA exposure . The prodrug 2-morpholinoethyl ester, named mycophenolate mofetil (MMF),
[6]
is converted to the active metabolite MPA by carboxylesterases 1 and 2 (CES1 and CES2) .
MPA is considered a safe drug even though some adverse events may occur, such as gastrointestinal
complications, myelotoxicity, susceptibility to infections and neoplasms [1,3] . Designed to reduce
gastrointestinal adverse events, the enteric-coated mycophenolate sodium salt (EC-MPS) has a delayed
[7]
release formulation that delivers mycophenolate in the small intestine . Due to enteric coating, EC-MPS
causes a slower absorption than MMF, and more variable time for MPA to reach maximal concentration .
[8]

MPA is extensively converted (about 90%) to the inactive 7-O-glucuronide (MPAG), by UDP-
glucuronosyltransferases (UGTs), mainly in the liver but also in intestine and to a minor extent in the
kidney . This process is mediated in the liver and kidney by UGT1A9, whereas UGT1A8 plays a key role
[9]
[9]
in the intestine with minor contribution from the other UGTs [Figure 1]. Since MPA and MPAG are
bound to serum albumin, an accumulation of MPAG may compete with free MPA for albumin and lead to
increased free MPA concentration in plasma [9,10] .

UGT2B7, with minor contribution of UGT1A8, mediates the biotransformation of MPA to its acyl-
glucuronide form (AcMPAG) [Figure 1]. This metabolite can inhibit the activity of IMPDH and is
[11]
therefore pharmacologically active . The cytochrome P450 (CYP) family also plays a role in MPA
biotransformation. The 6-O-desmethyl-MPA (DM-MPA) is a phase I metabolite of MPA produced in the
[12]
liver by the activity of CYP3A4, CYP3A5, and to a lesser extent by CYP2C8 .

MPAG and AcMPAG, but not MPA, are excreted in the bile. The incorporation of these metabolites into
hepatocytes is mediated by organic anion transport polypeptides (OATPs) [13,14] , which are membrane influx
transporters encoded by genes of the SLCO family. From the hepatocyte, MPAG and AcMPAG are excreted
in the bile via ATP-binding cassette subfamily C member 2 (ABCC2), also named multidrug resistance-
[17]
associated protein 2 (MRP2) [15,16] . ABC transporters are ATP-dependent drug efflux pumps . Another
important member is ABCB1 (also known as P-glycoprotein or multidrug resistance protein 1-MDR1),
[18]
which seems to play a role in MPA disposition .