Page 38 - Read Online

Genvigir et al. J Transl Genet Genom 2020;4:320-55 I http://dx.doi.org/10.20517/jtgg.2020.37 Page 323

The more common MPA-related adverse events are diarrhea and other gastrointestinal complications.
MMF can also cause myelotoxicity, especially leukopenia and anemia. Susceptibility to viral infections,
such as cytomegalovirus (CMV) and BK polyomavirus (BKV), also increases in patients taking an MMF-
containing triple therapy regimen. Patients with low tolerance to MPA may require dose reduction,
[1]
temporary interruption, or permanent discontinuation of the MMF treatment .

The contribution of pharmacogenomics in the response to immunosuppressive drugs has been widely
investigated. Several clinical studies have reported the influence of gene polymorphisms on the efficacy and
[1-3]
safety of MPA, suggesting their potential contribution to transplant patient management .

This review explores the pharmacogenomic studies that investigated polymorphisms in genes involved
in the pharmacokinetics and pharmacodynamics of MPA in kidney transplantation and the main clinical
outcomes and adverse events.

GENES RELATED TO MPA PHARMACOKINETICS
The pharmacogenomic studies involving genes related to MPA-metabolizing enzymes and transporters are
summarized in Tables 1 and 2, respectively.

CES1 and CES2
CES1 and CES2 play crucial roles in the hydrolysis of the MMF prodrug to MPA. CES1 is highly expressed
in the liver, while showing extremely low levels in the intestine. On the other hand, CES2 is mainly
[20]
expressed in the intestine, and also observed in liver tissue .

[21]
Fujiyama et al. evaluated the influence of CES2 variants in 5´UTR (-1548A>G, rs3890213) and intronic
regions (4595A>G, rs2303218 and 8721C>T, rs2241409) on MPA pharmacokinetics. They found no
association of these variants with MPA plasma concentration-time area under the curve, partial (AUC )
0-6
and total (AUC ) maximum plasma concentration (Cmax) and time required to reach the peak (Tmax) in
0-12 ,
80 Japanese kidney recipients at 28 days after transplantation. These variants were also not associated with
allograft rejection (AR) or diarrhea .
[21]

In a retrospective study with Brazilian patients a long time after transplantation (7.00 ± 5.71 years), CES2
8721TT genotype was associated with increased risk of AR (OR: 7.2; 95%CI: 1.1-46, P = 0.038), whereas the
CES1 356C>T (rs62028647) variant was not associated with AR .
[22]
CYP3A4, CYP3A5 and CYP2C8
The CYP enzymes CYP3A4, CYP3A5 and possibly CYP2C8 can catalyze the generation of the phase 1
metabolite DM-MPA, evident in human liver samples , suggesting that variants in these genes may be
[12]
involved in the clinical outcomes of MPA treatment.

Studies with certain variants in CYP2C8 (rs11572080 and rs10509681), CYP3A4 (rs2740574 and
rs35599367) and CYP3A5 (rs776746) found no association with MPA trough concentration/dose ratio (C/D)
and AUC in kidney transplantation [23,24] .
0-12

Although the CYP3A4 and CYP3A5 variants did not influence the clinical outcomes of MPA-based
therapy [23-27] , the results were less consistent regarding CYP2C8 variants.

CYP2C8 rs11572076 (G>A) variant was associated with increased risk of anemia (OR: 3.2, 95%CI: 1.7-6.2,
P < 0.001) in a study that evaluated 2,724 variants in 978 adult kidney or simultaneous kidney-pancreas
recipients . The authors also found no association between this variant and leukopenia, a finding later
[28]