Mycophenolic acid (MPA) as a tailored immunosuppressant : A narrative review of

pharmacokinetics and pharmacogenetic by MPA individualization therapy

Abstract

Mycophenolic acid (MPA) has been demonstrated to be a powerful immunosuppressant for

controlling rejection of allograft transplants. The pharmacokinetic profile of MPA varies
among individuals, which has an impact on their clinical outcomes and toxicity. Furthermore,
the genetic variability studies in PK-MPA should be investigated in order to better understand
the inter-individual variances in MPA response. Several studies in this chapter investigated a
significant genetic association on the pharmacokinetic behavior of MPA. However, other
studies have also shown inconsistent outcomes. There was still a paucity of large prospective
associations on genetic variation approaches. Therefore, we describe a summary of
pharmacokinetic profiles of MPA including absorption, distribution, metabolism, and
excretion as well as gene variations relevant to MPA-based treatment. The role of genetic
variation encoding MPA metabolization enzymes on drug efficay and safety is also discussed
in this chapter.

Introduction

Mycophenolic acid ((E) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl) -

4-methylhex-4-enoic acid), with the molecular formula C17H20O6, is a highly toxic
metabolite synthesized by various fungus Penicillium species. [1]–[6] It has 320,34 g/mol of
molecular mass and 141°C of melting temperature.[7] The major immunosuppressant agent,
mycophenolic acid (MPA), is considered to be an inhibitor of inosine monophosphate (IMP),
xanthosine monophosphate (XMP) and guanosin monophosphate (GMP).[8] This drug
inhibits the de novo guanosine nucleotide production pathway with high selectivity and
reversibility.[9] MPA has been extensively used to reduce acute and chronic allograft
rejection in transplanted organs such as kidney, heart, and liver transplantation, either alone
or in combination with other immunosuppressive medicines such as cyclosporine, tacrolimus,
and corticosteroids. [10][11] The addition of MPA to an immunosuppressive regimen will
increase organ transplant survival while also minimize the risk of morbidity associated with
concurrent corticosteroid maintenance treatment. [12][13]

MPA has a significant metabolic activity in hyperblastoid T cells. [14] By limiting de

novo purine nucleotide production and reducing both human T and B lymphocyte cell
activity, mycophenolic acid acts as a strong wide range immunosuppressant. [15] In contrast

1
to other cells, T and B cells proliferate depending greatly on the de novo process of purine
synthesis which cannot use the salvage pathway efficiently.[16] MPA could attenuate the
mitogenic and allospecific proliferation of cytotoxic T and antibody-producing B cells.[17]
Furthermore, adding guanosine or deoxyguanosine to lymphocytes restores the proliferative
inhibition and cytostatic activity of MPA. [18] MPA reduces glycosylation of cell adhesion
molecules (lymphocytes and monocyte glycoproteins) involving intercellular passage into
blood vessel endothelial cells, and may reduce leukocyte recruitment to areas of
inflammation and transplant rejection. [19]
MPA might also potentially stimulate CD70 expression and demonstrate T-cell-
dependent dosage mediated by anergy. [14][20] According to previous research, MPA
reduces leukocyte adherence while increasing monocyte apoptosis in inflammatory areas.[21]
MPA also inhibits the polarisation of CD-4 T cells in Th-17 cell response and suppresses
neutrophil formation by preventing the IL-17 producing T-cells following IFNμ DNA
methylation from naïve T cell activation. [22]–[24] A phenotypic analysis conducted with
MPA treatment in the renal transplant patient demonstrated a surge in CD4+CD25 (high)
Foxp3+ Tregs' negative stimulator expression. [25] Mycophenolic acid blocks cytokine-
dependent proliferation, such as cycline-dependent kinase and defective CDK-inhibitor
p27Kip1. [26] It also inhibits apoptosis and improves survival by not interfering with the
phosphorylation of extracellular signal-regulated kinase 2 and STAT5.[27]
MMF, a prodrug of MPA, acts as a selective inhibitor of the rate-limiting enzyme in de
novo GTP production, inosine 5'-monophosphate dehydrogenase enzyme (IMPDH), with a
preference for IMPDH II inhibition. IMPDH catalyses the conversion of inosine
monophosphate (IMP) to xanthine monophosphate (XMP), an enzyme involved in the
synthesis of guanosine triphosphate (GTP) (GTP).[28][29] GTP acts as a substrate for the
replication of ribonucleic acid (RNA), deoxyribonucleic acid (DNA), and proteins, all of
which are necessary for immune cell formation. [30] MMF currently operates via decreasing
intracellular GTP levels and altering G1-S cell cycle arrest. [31][32] Additionally, it has no
effect on the early events in the activation of interleukin-2-induced inflammatory cytokines.
[27] However, MMF reduces the synthesis of tetrahydrobiopterin and nitrogen oxide and
hence enhances the activity to fight inflammation.[33]

A. Pharmacokinetics profile of mycophenolate acid

MPA and MPAG pharmacokinetics profile were represented as a two-compartment
system with first order absorption depending on time. [34] A randomised controlled trial of

2
pharmacokinetic profile test with patients of renal transplants revealed MPA plasma
concentration-time profiles throughout a 24-week period. By using nonlinear mixed-effects
modelling, this study have been noted that free fraction of the MPA dose in renal transplant
patients was more complex increased over time following transplantation. [35] According to
another study, the area under the time concentration curve (AUC) for MPA can fluctuate by
up to 10-fold amongst patients taking the same dose of MMF. [36]
The population parameter of MPA pharmacokinetics was characterised as follows:
absorption rate constant (ka) = 4.1h (-1), central volume of distribution (V1) = 91 L,
peripheral volume of distribution (V2) = 237 L, clearance (CL) = 33 L/h, intercompartmental
clearance (Q) = 35 L/h, and absorption lag time = 0.21h. [35] The serum creatinine and
plasma albumin concentrations have a substantial effect on the plasma clearance and central
volume of distribution of MPA. Impairment of renal function, decreased serum albumin, sex,
and standard-dose ciclosporin were all significant factors.[35]
MPA exhibited circadian pharmacokinetic fluctuations that will affect interpatient
variability. [37] A study of MPA circadian exposure in stable renal transplant patients
showed that MPAG and AcMPAG steady-state levels decreased at night in comparison to
daytime. This influence, however, could not have affected the concentration of MPAG or
AcMPAG with cyclosporine or everolimus administration. [38] Another research found that
when MPA was given orally in the morning, the Cmax and AUC0-12 values were much
higher than when it was given at night. The relationship of MPA circadian exposure on
adverse effect outcomes among recipients after a month of transplantation was also
investigated. The prevalence of acute rejection was linked to a lower MPA trough value,
based on those study. When compared to individuals who do not have acute rejection,
patients with acute rejection had considerably lower MPA trough concentrations and AUC0-
12 during both day and night. [39]
Typically, the median AUC for unbound MPA remained unchanged. The overall
MPA AUC value was enhanced twice during the beginning therapy and four months
following transplantation. [40] The AUC values for the total concentration of renal allograft
patients with fixed doses of MPA were previously shown to be observed between early post-
transplantation (1-3 weeks) and stable graft function (after 3 months). [41] This was due to
the unbound MPA fraction rise over reduced serum plasma albumin. [42]
Total AUC only increased in patients which had impaired renal function in early after
transplantation. The time-related increase in MPA AUC is a reflection of improvement in
renal function. It is probably because the free MPA fraction has decreased, which leads to

3
slower clearance.[43] Other previous study showed that free concentrations of MPA will
increase in patient with renal impairment along with raised concomitant uraemia and MPAG
concentrations. [44] Furthermore, it is important to consider the possibility of
pharmacokinetic drug interactions with MPA. Multiple drug therapy are often prescribed in
renal transplant patient such as cyclosporin, tacrolimus and sirolimus. [45] Those drug
interaction could result in significant changes of the MPA pharmacokinetics due to its
metabolism pathway via the microsomal CYP-450 enzyme system. Most MPA concentration
data related to the use of MMF in combination with cyclosporin. [46] However, there has
been potential interaction between MPA and tacrolimus, with a substantial increase in MPA
exposure predose in renal transplant recipients with chronic mellitus diabetes. [47] Therefore,
other immunosuppressant drug could also change MPA drug exposure by influencing its
pharmacokinetic profile.

1. Absorption
Due to the poor absorption of MPA through the oral route, then it is manufactured as
two kinds of prodrugs: ester MMF mycophenolate mofetil (MMF) and enteric-coated
mycophenolate sodium (EC-MPS) to increase bioavailability. [48] On a equimolar basis, 720
mg ECMS b.i.d is proportional to 1000 mg of mycophenolate mofetil b.i.d.[49] ECMPS
should be administered on an empty stomach to reduce variance in MPA absorption between
doses. [50] MPA has a non-bioequivalent maximum plasma concentration (Cmax) after oral
administration of MMF and EC-MPS. MPA peak concentrations are generally reached within
1 to 2 hours following MMF oral administration, with the secondary absorption peak
occuring 8 to 12 hours. During the absorption phase, the secondary peak related to the
absorption properties of MMF/MPA was found which implies related to the drug's
enterohepatic recycling. Due to late enteric coating absorption, EC-MPS has a delayed period
of about 1.5–2.75 hours to reach its maximal concentration as compared to MMF. [36]
Moreover, MPA has a greater mean absolute bioavailability (80–90%) in healthy and renal
allograft recipient volunteers after oral administration of MMF and EC-MPA. [51] The
average apparent plasma half-life elimination of MPA is approximately 9 to 17 hours, which
is frequently given twice daily. [36] A research conducted in children with liver transplants
demonstrated a steady absorption rate of MPA at 1,7 hr-1, with volume distribution increase
of around 2,3 per cent in early post transplant. [40] Furthermore, MPA C0 levels were
reported 46% higher among the renal transplant recipients following EC-MPS than MMF.
[52]

4
 MMF is undetectable in plasma even after 10 min intravenous infusion cessation
which suggests a rapid change of MMF to MPA. MMF, 2-morpholinoethyl ester prodrug,
was rapidly underwent extensive presystemic deesterified by esterases in the gut, liver and
proximal small intestinal epithelium to form a pharmacologically active metabolite of
mycophenolic acid (MPA). [53] Oral administration of MMF (Mycophenolate Mofetil)
results in rapid presystemic bioactivation to mycophenolic acid via carboxylesterases (CES),
especially CES-1 and CES-2. The maximum concentration of its active metabolite, is attained
60 to 90 minutes after an oral dose administration. In the intestine, MMF is hydrolyzed to
MPA, N- (2-carboxymethyl) - morpholine, N- (2-hydroxyethyl) -morpholine and N-oxide
from N- (2-hydroxyethyl) -morpholine by CES-2.[53]
MMF distributed using a robust multi-compartment model that incorporates an EHC
gallbladder compartment employing zero-order absorption and atypical transit compartment
series such as first-order parallel and Weibull-type absorption. [54] [55] Following transit
into the intestine, MPA is absorbed into the central compartment by the constant rate of
absorption. Furthermore, there was cleaning between MPA compartments from the peripheral
compartments. [56]
A healthy voluntary pharmacokinetic study has indicated that the average oral
bioavailability of MMF at a Cmax of (24,5±9,5) μg/mL in was 94 percent at AUC values
(63,9±16,2) μg•h/mL after single dose. In comparison to renal transplant patients receiving
daily MMF, Cmax was (12.03.82) g/mL with an AUC of (40.811.4) g•h/mL after 5 days
transplantation. After 3 months of transplantation, Cmax will lead to increasing in
proportional dose trends by (24.1±12.1) μg/mL with AUC (65.3 ±35.4) μg•h/mL.
Nevertheless, the presence of food will reduce MPA Cmax by 40%. [57]
The enteric-coated sodium mycophenolate (ECMS) was developed to highly dissolve
at pH >5.5 in the small gut with absolute bioavailability of 72% in order to diminish the
upper gastrointestinal side effects of mycophenolate mofetil. [58] High carbohydrate diet
could delay Tlag and Tmax by 3.5 to 5 hours respectively and reduce of MPA Cmax by 33%.
[59] In a study comparing EC mycophenolate sodium and mycophenolate mofetil in stable
renal transplant recipients, it was discovered that the ECMS had a higher trough
concentration and a longer time of maximum concentration (tmax) than the mycophenolate
mofetil.[60]

3. Metabolism

5
 The oral and intravenous mycophenolate mofetil (MMF) are hydrolysed by liver
carboxylesterase activity in the intestine. This enzyme could alter MMF as certain other
metabolites include N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine and
N-oxide portion N- (2-hydroxyethyl). In human liver microsomes, MMF in vitro hydrolysis
rate is higher than in human intestinal microsomes. [53]
MMF penetrates the liver cells through the portal vein and mainly metabolized into
active drug of mycophenolic acid (MPA) by carboxylesterases liver enzymes (CES) 1 and 2.
Therefore, MPA is mainly extensively metabolized (about 90%) to the pharmacologically
inactive 7-O-glucuronide (MPAG) in liver by UGT1A9 in term of inhibiting IMPDH-2
activity. These phenolic glucuronidated metabolite (MPAG) is transported from liver cells
into bile via the ATP-binding cassette transporter MDR1-related protein 2 (MRP-2). [67]
Furthermore, biliary MPAG enters the gastrointestinal tract and hydrolyzed back to MPA
under the bacterial β-glucuronidase catalytic action that is shed from the gastrointestinal
flora. Then, MPA will reabsorb into the bloodstream followed the systemic enterohepatic
circulation (EHC) pathway.[63] Enterohepatic recirculation contributes approximately 40%
of cumulative MPA exposure. Due to the EHC route, pharmacokinetic investigations in
plasma concentration-time profiles have indicated additional peaks generally within 6-12
hours after administration of MMF orally.[36]
Additionally, the cytochrome P450 (CYP) family is involved in MPA
biotransformation. The 6-O-des-methyl-MPA (DM-MPA) was a minor quantity of phase I
metabolite generated by family liver cytochrome P450 (CYP) enzymes (DM-MPA).
CYP3A4, CYP3A5, and to a minor extent CYP2C8 generate the metabolite 6-O-desmethyl-
MPA (DM-MPA) mostly in the liver. It is subsequently conjugated to produce two
glucuronides, which comprise extremely tiny portions of MPA. It was not feasible to
determine their structural identity, although they are considered to be 4-O-phenyl and 6-O-
phenyl DM-MPA glucuronides. [68]
Phase II MPA glucuronidation is a primary metabolism mediated by UDP
glucuronosyl transferases (UGTs) in the intestine and liver. Primary enzymes involved in
MPA glucoronidation were Uridine 5ʹ-diphosphate (UDP)-glucuronosyltransferases enzymes
such as UGT1A8 and UGT1A9 with minor roles for UGT1A1, 1A7 and 1A10. UGT1A8 and
UGT1A10 are predominantly expressed extrahepatically and are hence involved for
gastrointestinal metabolism of MPA. UGT1A8 and UGT1A10 are expressed only extra-
hepatically and thus are responsible for MPA metabolism in gastrointestinal tract. [69]

6
Whereas, the hepatic metabolism of MPA also includes UGT1A8, UGT1A9, and UGT2B7.
[70]
MPA, which is released by the bile to the gut via the UGT, has many secondary
metabolites: 7-O-MPA-β-glucuronide (MPAG, inactive); acyl-glucuronide MPA (AcMPAG);
and glucoside of 7-O-MPA.[71] 7-0-glucoside does not have an in vitro IMPDH inhibiting
function. Ac-MPAG (metabolised by UGT2B7 with a minimal contribution from UGT1A8)
is a potent pharmacological metabolite of acyl glucuronide which may limits the rate of
IMPDH. Ac-MPAG may be detected at levels equivalent to the parent drug in pre-dose
plasma samples (MPA). As a result, AcMPAG is comparable to MPA monitoring in terms of
potency. However, since Ac-MPAG is a weaker inhibitor of rhIMPDH II than MPA, it would
be less potent pharmacologically. [72] Ac-MPAG promotes the release of cytokines from
mononuclear leukocytes and may contribute to the aetiology of MPA's unfavourable
gastrointestinal effects. [73] MPAG and AcMPAG are also organic anion transport
polypeptides (OATPs) substrates. Prior study discovered that OATP has considerably
accumulated human embryo kidney (HEK) cells expressing OATP1B3 and OATP1B1. [74]

4. Elimination and Clearance

MPA is largely removed as MPA-7-O-glucuronide (MPAG) with some kind of
quantity of MPA (>90%) in the urine. ABCC2 may be involved in this process, which is
mediated by active tubular secretion and glomerular filtration. [75] MPAG and Ac-MPAG,
get excreted in bile. These metabolites incorporate into hepatocytes cells and mediated via
organic anion transport polypeptides (OATPs). OATP are membrane influx transporters
encoded by genes of the SLCO family. The bile excretion of MPAG and Ac-MPAG is
mediated via canalicular Multidrug Resistance-associated Protein 2 (MRP-2) encoded by the
ATP-binding cassette subfamily C member 2 (ABCC2) gene which are ATP-dependent drug
efflux pumps. [76] Another major gene that encodes for the multidrug resistance protein1-
MDR1, significantly impacts MPA metabolism.[77]
MPAG clearance from plasma was rapid but biliary excretion was delayed in Eisai
hyperbilirubinemic rats (EHBRs) with MRP2 mutations. Therefore, it is suggesting that
MPAG and Ac-MPAG transport via MRP-2 on the bile canalicular membrane. [78] MRP2 is
also abundant in the brush border membrane of the renal proximal tubule, suggesting that it
may participate in the renal transport of MPAG. Human renal organic anion transporters
hOAT3 (SLC22A8) has a key function in MPAG absorption and renal tubular secretion in
previous study. [79] Further studies using xenopus oocytes discovered that OAT1 and OAT3

7
are also involved in the secretion of MPA and its metabolites in the kidneys. The
gastrointestinal toxicity of MPA can be related with those biliary excretion mechanism of
MPAG.[80]
MPA exposure in renal transplantation is significantly affected by the large patient
variation and the steady rise in MPA concentration over time. About 44% to 38% decrease in
average clearance of MPA was observed throughout the first six months to one year post
transplantation. Previous study conducted by Reiner et al. reported that time-dependent
changes to MPA exposure in renal allograft patients are due to a combination between an
increased of creatine clearance, albumin, hemoglobine and a decreased of MPA clearance.
Furthermore, MPA levels obtained at 6 months after transplantation also impact
pharmacokinetic values.[81] Increased albumin concentrations would presumably have
resulted in less MPA clearance, hence it is possible that MPA clearance decreased because of
a reduction in the free drug fraction.[34] These trend might also similar with the effect of
hemoglobin on MPA clearance.[82] But the mechanism is still unclear, since MPA levels in
red blood cells make up a very minor portion of overall MPA concentrations (0.001%).[83]

B. Genetic polymorphism affecting mycophenolic acid pharmacokinetics

The genetic variation studies within gene involved in MPA biotransformation
pathways has been widely investigated. Previous clinical evidences have investigated gene
polymorphisms involved in the interindividual pharmacokinetics variability of MPA. The
metabolism of MPA occurs both in the liver and in the intestines by an enzyme system called
UGT, including UGT1A8, UGT1A9, UGT2B7, and UGT1A10. MRP-2, a drug transporter, is
also involved in the transit of MPAG and bilirubin from hepatocytes to the bile. The
polymorphism in this transporter site could potentially impact the absorption, distribution,
and EHC of MPA. A pharmacokinetic studies demonstrated that MRP-2 polymorphisms have
shown a modest effect on MPA AUC values. Therefore, genetic variation may mainly affect
to the personalized clinical outcomes and adverse events in transplant patient management.
Some studies reported the impact of genetic variation on the MPA PK-profile are
summarized below.
1. Carboxyl esterase (CES1 and CES2)
The human carboxyl esterases (CES1 and CES2) are required for the conversion of
the ester MMF prodrug to MPA. The CES1 family is the highly expressed in the liver, while
CES2 showing only predominated expressed in the human intestine. CES genes have a wide
range of polymorphisms. A preliminary experiment on human liver microsomes found that

8
the hydrolytic activity of MPA was inhibited by three different CES inhibitors named
phenylmethylsulfonylfluoride, bis-p-nitorophenylphosphate, and diisopropylfluorophosphate.
[53] However, a study in renal transplant patients with repeated-doses of MMF demonstrated
that no association between CES2 rs3890213 and rs2303218 variants on MPA concentrations
among individuals in short term post-transplantation. There was no significant effect of CES2
A4595G, C8721T, or A-1548G genotype on MPA pharmacokinetics. [84] Additionally, no
CES variations were related with allograft rejection. A retrospective analysis revealed that the
CES2 8721TT and CES1 356C>T (rs62028647) genotypes were not significantly linked with
the likelihood of allograft rejection in long-term renal transplant recipients in Brazil.[85]

2. Cytochrome (CYP) 450 (3A4, 3A5 and 2C8)

The CYP enzymes plays an important role in catalyze the phase 1 metabolite of DM-
MPA. The genes include CYP3A4, CYP3A5, and CYP2C8, which are all of the genes known
to be implicated in the effectiveness of MPA therapy.[68] CYP3A5 *1 allele or the
CYP3A5*3/*3 genotype did not influence the pharmacokinetic profiles (trough
concentration/dose ratio and AUC) in renal transplantation with MPA-based therapy. [86]
DOMINOS trials have reported that CYP2C8 rs11572076 GG genotype was significantly
associated with a lower risk of MPA-related leucopenia among renal transplant allograft.[87]
However, a study involving 2724 SNPs among 978 renal transplant recipient, has found a
correlation between CYP2C8 rs11572076 variant and incidence of hematologic toxicity.[88]
Recent data suggest a minor involvement of CYP2C8 and CYP2J2 enzyme in MPA
oxidative metabolism. The variant of CYP2C8*3 and CYP2J2 c.−76G>T was involved in the
incidence of adverse events in renal transplant recipient who treated with combination of
immunosuppressant tacrolimus, enteric‐coated mycophenolate sodium, and prednisone for 90
days post transplantation. [89] However, those cohort study reported that CYP2C8*3 variants
was not associated with the mycophenolate sodium dose and delayed graft function episodes.
[89]
3. UDP-glucuronosyltransferases (UGT1A and UGT2B gene family)
The nine UGT1A genes (1A1, 1A3-1A10) encode proteins involved in phase II MPA
metabolism and are located on chromosomal band 2q37. UGT1A7, UGT1A8 and UGT1A10
are most abundant in other tissues, such as the intestine. The expression of UGT1A1 and
UGT1A9 are in the liver and extrahepatic tissues mainly in the kidney, as well as lesser
extent in colon, adrenal and bladder which involved in MPAG formation via glucuronidation.
Each UGT2 isoform enzyme are expressed in human tissues including liver, small intestine,

9
and kidney. [90] UGT2B7 and UGT1A8 play in major role in acyl (AcMPAG) glucuronides,
while UGT1A8 and UGT1A10 are involved in minor role of MPAG disposition. [91][92][72]
Liver UGT1A1 is considered the most widely expressed of the human UGT enzymes
and only responsible for bilirubin glucuronidation activity.[93] However, UGT1A1*28
(rs3064744) alleles have shown no association with the MPA side effects among adult
patients. [39] The UGT1A7 alleles were associated with an enzyme deficiency regarding
glucuronidation or transcription activity and may result in a higher risk of drug-induced side
effects. [94] An invitro study demonstrated that the UGT1A7 622T>C genotype could
increase the activity of UGT1A7. [94] Patients with the UGT1A7 622CC genotype had a
greater dose-dependent MPAG AUC0-12, resulting in MPAG accumulation.
UGT1A7.C.622CC (rs11692021) genotype was substantially positively linked with the dose-
adjusted MPAG AUC0–12h in Chinese renal allograft recipients who were either
homozygous for the 622T mutation or heterozygous for the −440C/−331T mutation
(P=0.030). [95] As a result, this will increase the incidence of infection and other possible
adverse effects, and may need a reduction in MMF dose. Other results conducted in adult
renal transplant patient reported that UGT1A7 rs7586110 (-57T>G), UGT1A7*2 and
UGT1A7*3 have a low-activity variant and not linked to any gastrointestinal toxicity,
leukopenia and pharmacokinetics profile of MPA.[96]
In the study of Chinese renal transplant patients, the variation UGT1A8 rs1042597
(p.Ala173Gly, c.518C>G) known as UGT1A8* polymorphisms was related with MPA
pharmacokinetics. UGT1A8*3, *5, *7,*8 and *9 polymorphism was found to have a reduced
AcMPAG and MPAG in human embryonic kidney cells. [91] Another missense variant,
UGT1A8*3 rs17863762 (p.Cys277Tyr, c.830G>A) have been proved to decrease the
production of MPAG in vitro. [97] However, this variation has no influence on the
pharmacokinetics of MPA in the paediatric or adult groups in terms of its low frequency. [97]
UGT1A8*2 polymorphism also has required for inhibition of UGT1A8 activity, as well
as showed a negative effect on MPAG formation in vivo. UGT1A8*2 (518C>G) variant was
demonstrated to be associated with a lower dose-adjusted AUC0–12 h of MPAG (P=0.004).
[95] Patient carrying UGT1A8*1/*2 and *2/*2 reported a decreased of MPAG dose-adjusted
AUC0-12 by 22% compared to those carriers UGT1A8*1/*1. [70] Meanwhile, a study
showed MPA day time dose-adjusted trough concentrations in the *1/*1 and *2/*2 carriers
was higher than those in the *1/*2. Those study involving kidney transplant recipients also
found that UGT1A8*2 variant was not associated with MPA or MPAG pharmacokinetics.

10
[98] These variants were also related with increased MPA AUC0-12 in individuals treated
with cyclosporine due to their suppression of UGT1A8 enzyme activity. [99]
A long term cohort retrospective study confirmed that patient with UGT1A8*2 variant
carrier (C518G and 518GG genotype) given MPA co-treated with cyclosporine based-therapy
has a protective factor against the MPA gastrointestinal side effect. CsA has a pivotal role to
inhibits the excretion of MPA metabolites (AcMPAG) into the bile through mediated by
MRP-2. AcMPAG is thought to be implicated in intestinal mucosal toxicity via a secondary
immune mechanism. [100]
Another study found that UGT1A8 was related to a greater risk of Gastrointestinal
Symptoms Rating Scale (GSRS) scores in renal transplant patients undergoing MPA
medication. UGT1A8 *2/*2 (c.518GG) genotype carriers were substantially related with the
severity of gastrointestinal problems (abdominal discomfort, acid reflux, indigestion,
diarrhoea, and constipation) as compared to UGT1A8 c.518C allele carriers. Non-carriers of
UGT1A8*2 had more diarrhoea than heterozygous or homozygous carriers of the gene.[101]
Renal transplant patient carrying UGT1A8 (-999C > T, codon 255A > G, codon 277G > A)
genotype given with high dose of MMF showed a higher risk in the occurrence of infections.
[102] The elevation of MPA levels may be related to the inhibition of enzyme activity. Other
investigations have shown that UGT1A8 c.518C>G and c.830G>A in patients of renal
transplants have not been related with a rejection of allografts, leukopenia and anaemia.[103]
[99][104]
UGT1A9 promoter SNPs have a key influence in the MPA pharmacokinetics as well as
adverse effect. In the human liver, UGT1A9 is the most substantial enzyme involved in the
conversion of MPA to MPAG. An invitro study have identified that UGT1A9 (C-440T/T-
331C) variants are potential influence the MPA pharmacokinetics in renal allograft recipients
which implicated the great inter-individual differences. [105]
Various promoter SNPs of UGT1A9 such as C-2152T (rs17868320), T-275A
(rs6714486), C-440T (rs2741045)/T-331C (rs2741046) and C-665T. were significantly
influenced the expression of UGT1A9 enzyme. In compared to non-carriers, UGT1A9 in
carriers of rs17868320 (C-2152T) and rs6714486 (T-275A), both of which are infrequent in
Asian populations, showed 1.4 and 1.6 times greater levels of UGT1A9 expression and
activity in liver microsomes. Renal allograft patient with those polymorphism had been
associated with low AUC and C0 of MPA due to high activity of UGT glucuronidation as well
as suppress the enterohepatic recirculation pathway which result in decreases of MPAG
deglucuronidation. [106] Meanwhile, a cohort study in patients treated with an MMF and
11
cyclosporine regimen discovered that the UGT1A9 c.-440 TT and -665CT genotypes were
linked to greater MPA exposure (AUC0-2, 0-4, 0-12 or C/D). [105] A conflicting result
conducted in Chinese renal allograft recipients with UGT1A9-1818CC genotypes showed a
lower MPAG AUC0-12 on tacrolimus-based therapy. [95]
Zhang et al. discovered that another SNP UGT1A9*1b (rs3832043) has related enhanced
enterohepatic circulation of MPA by increasing both in vitro and in vivo glucuronidation.
Patients who had at least one allele without T deletion had a greater dose-adjusted AUC6-12
(an indicator of enterohepatic recirculation) than those who had T deletion. [107] Other
clinical studies in kidney transplant patients found that UGT1A9 rs3832043 (-118delT),
rs72551330 (c.98T>C), and rs2741049 (I399T>C or IVS1 + 399T>C) had no effect on MPA
or MPAG pharmacokinetics. [107]–[109] A study involved 338 patients indicate a higher
exposure MPA AUC0-112 in UGT1A9 c.98T>C carrier accordance to activity and minor
allele frequency was low around 2%. [99]
Moreover, recent study confirmed that UGT1A9 of -275T>A/-2152C>T was associated
with therapeutic MPA exposure and greater severity of gastrointestinal side effects (diarrhea,
stomach discomfort, reflux, heartburn and constipation) among patients receiving tacrolimus,
corticosteroids and MMF-based immunosuppressant therapy. While in patient received two
combination immunosuppressant MPA dan tacrolimus reported higher risk of allograft
rejection (OR: 13.3, 95%CI: 1.1-162.3, P = 0.042). Other polymorphism of UGT1A9
rs6744284CC genotypes impact the increased of constipation severity after 7 days
transplantation. [101] In a contrary other research discovered that UGT1A9*3 was related
with increased MPA exposure in patients receiving MMF and tacrolimus/cyclosporine
concurrently.[70] Patients with UGT1A9 promoter SNPs (-2152T/-275A) had a higher
prevalence of renal rejection as well. [110] A study among pediatric kidney patients
demonstrated that UGT1A9 -331T>C (rs2741046) allele was likely increased the MPA
exposure and leukopenia occurrence. [104] Additionally, in individuals with normal renal
function, UGT1A9*3 was related with increased MPA and AcMAPG exposure. [70]
A total of 8 nonsynonymous polymorphism in the first exon UGT1A8 have been involved
in the MPAG formation namely S43L, H53N, S126G, A144V, A173G, A231T, T240A, and C277Y. 
Some UGT1A8 variants may constitute the high interindividual variability differences in
MMF pharmacokinetics. UGT1A8*3 (C277Y, rs17863762), *5 (G173A240), *7 (A231T), *8
(S43L, rs372427845), and *9 (N53G) amino acids were found to have a significant impact on
substrate binding and enzyme activity. They were related with a reduction in the production
of MPAG and AcMPAG in human embryonic kidney cells. Even though, the UGT2B7*2

12
variant has a minimal action but one alleles of UGT2B7*2 Y268 demonstrated efficient as
catalytic compare to UGT2B7*1 (H268).[91] However, neither UGT1A8 nor UGT2B7 showed
a significant association on MPA plasma level in Japanese renal transplant recipients. [98]
The MPA therapeutic regimen involves a great deal of gastrointestinal adverse effects.
However, when examined on the Gastrointestinal Symptom Rating Scale (GSRS), the
UGT2B7 802C>T polymorphism demonstrated fewer gastrointestinal side effects as
compared to the wild type (p=0.009).[111] In addition, a study observed that renal transplant
patient who received combination regimen of MMF and cyclosporine with carrying
UGT1A8*2 allele carriers (C518G and 518GG genotypes) have lower risk of diarrhea
incidence as compare to UGT1A8*2 non carrier (CC518 genotype). [100]
UGT2B7 is the major enzyme implicated in AcMPAG formation. Invitro and invivo
study using human liver microsomes proved that UGT2B7 -842AA genotype have associated
with the larger AcMPAG production compared to G-842A genotype. Patients who received
MMF and sirolimus in combination had a higher level of AcMPAG AUC0-9 at month 1 and
3 after transplantation when they had the UGT2B7 genotype. A research including
individuals with UGT2B7 who were administered MMF in combination with tacrolimus or
cyclosporine found no relationship between AcMPAG exposure and UGT2B7 mutation.
Furthermore, neither the UGT2B7 842G>A nor the 802C>T variations had a significant
influence on AcMPAG exposure in kidney transplant patients receiving therapy with or
without corticosteroids. Corticosteroid might result in decreased level of MPA by inducing
the glucuronidation pathway.[112] Patient with UGT2B7*2, rs7439366 and the UGT2B7 -
138A variant have influenced in MPA pharmacokinetics by increasing the AcMPAG AUC
and ratio of AcMPAG:MPA. [113]
Other study evaluated the role of UGT2B7 802TT towards the MPA pharmacokinetic
profile. These genotypes are related with a decreased average MPA Cmax time at night and a
higher AUC0-12 MPA level. [98] However, UGT2B7 -79G>A variant (in LD with 802C>T)
was not linked to MPA exposure which exhibit the transcriptional activity reduction of
reporter gene in Caco-2 and HepG2 cells. [114]. The association study of UGT2B7 802T
allele towards MMF pharmacokinetic in pediatric patient setting have also investigated. A
finding showed that MMF apparent oral clearance (CL/F) is higher in UGT2B7 802 C/T and
802T/T carriers than that for those with UGT2B7 802 C/C after 2 months of postoperative
surgery. [115]
4. ATP-binding cassette (ABC) B1, C2 and G2 sub family

13
 MDR1 (ABCB1), MRP2 (ABCC2) and BCRP (ABCG2) are the member of ATP-binding
cassette (ABC) transporter family which predominantly expressed in apical membranes of
physiological barrier tissues such as intestine, liver and kidney. [116] ABCB1 (also named P-
glycoprotein/Pgp) plays a crucial function in the metabolism of MPA. [117] Besides, ABCC2
is a substrate for major glucuronide metabolites of MPA. The excretion of MPAG and Ac-
MPAG from proximal renal tubule or through bile duct is mediated via ABCC2 gene. [118]
ABCG2 also shows as a major MPAG and AcMPAG uptake transporter which distribute
drug from human liver into bile duct. [119]
ABCB1 gene lies than 25kb which located on chromosome 7q21.12 [UCSC Genome
Browser, March 2006 Assembly (hg18)]. [120] Patient receiving MPA combined with
cyclosporine or tacrolimus regimen showed an independent result. Cyclosporine has been
identify as an efflux transporter substrate of P-glycoprotein encoded by ABCB1 gene. [121]
Unlike tacrolimus, cyclosporin also inhibit ABCC2 and OATPs which might suppress MPA
enterohepatic recycling in order to reduce the MPA total clearance and increase MPAG-
AUC.[78]
In adult patient receiving tacrolimus, ABCB1 c.3435T allele showed a significant
requirement for MMF dose reduction due to MPA-related diarrhea. Nevertheless, no
differences in dose-adjusted MPA AUC between individual carrying ABCB1 c.3435T
compared to c.3435CC genotype.[39] The ABCC2 c.-24C>T SNP was significantly related
with greater MPA trough concentrations between day 42 and one year after transplantation in
a study including renal transplant recipients receiving tacrolimus-based treatment. The
ABCC2 c.-24C>T SNP was linked to a greater rate of diarrhoea in the first year after
transplantation. [122]
ABCB1 c.3435T genotype affects a wide range of drugs absorption with a higher
systemic and intracellular concentrations through the reduction of ABCB1 protein expression
activity. [123] Furthermore, the ABCB1 c.2677T allele, as well as c.3435T/c.2677T/c.1236T,
has been linked to a greater risk of allograft rejection in Caucasian patients receiving MMF
and cyclosporine. [124]. MDR1 C3435T polymorphism might also be associated with the
MPA side effect of diarrhea. Therefore, patient with multidrug resistance 1 (MDR1) C3435
TT genotype should require a significant lesser dosage of MMF compared to those with the
CC genotype. [39]
ABCC2, an efflux transporter, is responsible for MPAG and AcMPAG excretion in
bile canalicular duct. Multidrug resistance-association protein 2 (MRP2), encoded by these
gene may be involved in active transport of MPA via extensive enterohepatic circulation.

14
[125] ABCC2 rs717620 was associated with MPA concentration/dose ratio among renal
allograft recipients. [73] Other study demonstrated the impact between ABCC2 rs717620 (-
24C>T) and rs3740066 (-3972C>T) on MPA PK of renal transplant recipients received
tacrolimus and corticosteroid in combination with MPA was related with MPA exposure
reduction. Therefore, patient carrying those polymorphism could protect renal transplant
recipients from liver problems. [64] Patient carrying genotype combination both SLCO1B3
(334T>G) TT and ABCC2 (-24C>T) CC have a significant impact to the lower MPA
clearance. The polymorphism between the SLCO1B3 (334T>G) TT and ABCC2 (-24C>T)
CC genotypes results in considerably reduced MPA clearance in recipients. In contrast,
patient with ABCC2 1249G>A polymorphism indicate the more significant higher of Ac-
MPAG plasma level than wild type. [126]
ABCC2 transporter is known inhibited by cyclosporine. ABCC2 -24C>T was shown
to have no significant association with MPA, MPAG, or Ac-MPAG exposure levels in a
pharmacogenetic investigation of Chinese renal transplant patients receiving cyclosporine.
These result was due to the interaction between ABCC2 genotype with cyclosporine which
could masked the gene function. Recent study suggests that immunosuppressant regimen of
cyclosporine, tacrolimus or sirolimus could not affect the MRP2 transporter of MPA.[107]
ABCC2 rs717620 (c.-24C>T) which located in the 5´-UTR of chromosom 10 exhibit
a greatly tissue specific and rely on miRNA expression (epigenetic) as regulatory factors.
[127] ABCC2 rs717620 also related with the level exposure of MPA in adult renal transplant
recipients treated with one year regimen of MMF and tacrolimus. Patient who are non-carrier
ABCC2 rs717620 and mild liver dysfunction, reported a significant reduced in MPA level
exposure at day 7 compare than those with normal liver function. [122]
Furthermore, at 3 month post-transplantation, the MPA AUC was statistically
significant decrease in Chinese patient with ABCC2 c.-24T variant carrier on macrolides
regimen. On contrary, patient with T carrier who treated with cyclosporine therapy showed a
higher MPA AUC at first week post-transplantation. [128] A study found that MPA level
could increase after 45 days post-transplantation regarding ABCC2 c.-24T. Those gene
polymorphism also influenced the level of MPA with 17%-23% significant higher at 6 weeks
post transplantation. These mechanism could be explain by the genotype influence towards
the enhanced of protein expression/activity and enterohepatic recirculation pathway. The
increased of MPAG enterohepatic recirculation could also induce gastrointestinal outcome. A
clinical study in patient with sABCC2 c.-24T allele showed a higher incidence of diarrhea
after first year transplantation might be associated with the local exposure.[122]

15
 A kidney donor carrying A allele of the ABCC2 rs2273697 (c.1249G>A) showed a
MPA shorten peak and early exposure due to the increased of renal elimination. In addition,
ABCC2 c.1249A allle with cyclosporine-based treatment in renal transplant patients reported
a decreased proportion of MPA AUC0-2 by 49%. [129] Other studies found that the ABCG2
rs2231142 and ABCG2 rs4491984 variations had no effect on clinical outcomes (graft
function) and MPA or MPAG level exposure in patients taking immunosuppressive drugs.
[130]

5. The human solute-carrier organic (SLCOs) genes

Organic anion transporting polypeptides (OATP) protein encoded by human solute-
carrier organic (SLCOs) genes namely SLCO1B1 (OATP1B1), SLCO1B3 (OATP1B3) and
SLCO2A2 (OATP1A2) are major transporter in disposition of MPA and its metabolite
(MPAG) into hepatocytes. [74] This protein contribute as a drug transporter with ABC
protein but not depend directly on using cellular ATP. [131] OATP1A2 is also found in the
brain, colon, and distal nephron of the renal as well as in human liver.[132] The gene
polymorphism of OATP1B3 showed increased MPAG absorption and reduced OATP1B1
expression in human embryonic kidney cells. MPA or MPAG accumulation was not
influenced by OATP1A2 (SLCO1A2). Therefore, patient treated MMF combined with
tacrolimus or sirolimus and carrying SLCO1B3 334T>G/699G>A polymorphism indicated a
significant association with pharmacokinetic. This effect was not identified in patients with
same those SNPs who were treated with MMF and cyclosporine. [74] A study in healthy
Chinese adult patient stated that MPA AUC4-12 was lower in those carrying SLCO1B3 334T
allele but not in those with 334G allele and co-administered with prednisone. In this study,
the confounding factor such weight and concomitant use of steroid must be considered as a
standard diagnosis for genetic associations.[133] Other investigation has reported that
SLCO1B1*5 allele could decrease the transport of MPAG and AcMPAG which result in
adverse drug reactions protection.[134]. A significant higher MPAG AUC0-12 level also
reported in SLCO1B1*1/*1 as comparation to SLCO1B1*15 patient carrier. Another study
showed a significant lower of MPA transport in recipients with SLCO1B1*5 allele.[126]
Other study among renal transplant patients co-treated with MPA and cyclosporine conclude
that ratio of MPAG/MPA AUC4-12 levels were significant greater in those with SLCO1B3
767GG genotype compared to GC genotype. [74]

16
 Cyclosporine have been demonstrated as a potent inhibitor of OATP1B1 gene. A
clinical investigation of French patients who did not receive cyclosporine-based Therapy
indicated that the SLCO1B1 c.521C allele (SLCO1B1*5) was associated with a decreased
risk of MPA-related complications such as leukopenia, anaemia, thrombocytopenia,
diarrhoea, nausea, vomiting, or infection. Moreover, these gene variants were related with
decreased hepatic absorption of MPAG and AcMPAG in vitro. This could result in lower
enterohepatic recycling pathways in order to reduced the MPA level exposure and adverse
events.[134]
Invitro study using OATP- transfected human endocrine kidney (HEK293) cells
demonstrated an association of OATP1B3 (SLCO1B3) c.334G-c.699A haplotype with a
lower MPAG uptake. Similarly, a clinical trial of patients receiving tacrolimus or sirolimus
demonstrated that the SLCO1B3 c.334GG genotype was associated with a reduction in MPA
peak concentration and an increase in MPAG/MPA ratio. The lower expression of OATP1B3
activity will result in a reduction in the hepatic uptake of MPAG. SLCO1B3 c.334GG
genotype carriers will also impact the MPA reabsorption via enterohepatic pathway. [74] A
study in Japanese patient given tacrolimus concluded that SLCO1B3 c.334GG (699AA)
genotype was associated with MPA enterohepatic recirculation by higher MPA AUC6-12 at
day 28 post-transplantation. Other gene variations of the SLCO2B1 c.-71T>C (rs2851069)
and SLCO2B1*3 (rs2306168), had no effect on the MPA pharmacokinetics or clinical
outcomes of tacrolimus-based treatment in the early or late post-transplantation periods.[126]

Conclusion

We summarized the effect of genetic variations on the pharmacokinetics and

pharmacodynamics of MPA in kidney transplant patients. Numerous SNPs were discovered
for carbonyl esterases, cytochrome P-450, uridine diphosphate glucuronosyltransferase, ATP-
binding cassette and solute-carrier organic gene family. Individualized therapy may help to
increase the effectiveness and minimize the toxicity of mycophenolate acid. Multiple
medication combinations, and a lack of relationship consistency across studies have also been
significant challenges for MPA pharmacogenomics. Furthermore, pharmacogenomic
investigations are still required to understand the impact of specific gene to MPA efficacy
and safety profile.

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