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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 343

an increased renal elimination. Moreover, the authors showed that the combination of cyclosporine and
ABCC2 c.1249A allele reduced MPA AUC by 49%, an additive effect of this immunosuppressant.
0-2

Lack of association of ABCC2 c.-24C>T, 1249G>A, c.3972C>T, and rs8187694 (3563T>A) variants with
MPA or MPAG pharmacokinetics was reported by other studies [14,24,37,39,40,45,48,49,65,66] .

[62]
Regarding clinical outcomes, Naesens et al. found that ABCC2 c.-24T allele carriers had more frequent
episodes of diarrhea that non-carriers in the first year after transplantation. The authors considered the
limitation of the sample size but stated that an increased enterohepatic recirculation of MPAG associated
with the ABCC2 c.-24C>T variant could lead to diarrhea. It is important to mention that the local exposure
and not the systemic concentration of MPA is relevant for gastrointestinal adverse events. Moreover,
AcMPAG, produced in gastrointestinal cells and also substrate of ABCC2, contributes to cell toxicity [3,15] .

Other studies failed to confirm associations between ABCC2 polymorphisms and clinical outcomes
(AR, DGF, graft function) or MPA-related adverse events in pediatric or adult kidney recipien
ts [13,22,24,25,27,29,30,34,39,49,65] .

ABCG2
Brazilian, Chinese, and North American cohorts have been studied regarding two ABCG2 variants in
pediatric and adult kidney transplant patients [Table 2]. The ABCG2 c.421C>A (rs2231142) variant leads
to the amino acid exchange Gln141Lys, whereas ABCG2 -20 + 11790G>A (rs4491984) is an intronic
polymorphism.

The investigations pointed out that these variants did not influence MPA or MPAG exposure or clinical
outcomes during treatment with different immunosuppressive therapies [24,27,30,37,38] .

SLCO1B1, SLCO1B3 and SLCO2B1
OATPs additionally contribute to drug disposition, with ABC proteins; however, OATPs do not depend
directly on using cellular ATP [67,68] . OATP1B1 and OATP1B3 are mainly expressed in the liver, while
OATP1A2 is expressed in the intestine, biliary cells of the liver, and distal nephron of the kidney .
[67]
In studies with OATP-transfected human embryonic kidney (HEK) cells, MPAG uptake, but not MPA, was
enhanced by OATP1B3 (SLCO1B3) and to a lesser extent by OATP1B1 (SLCO1B1). MPA or MPAG uptake
[13]
[14]
was not influenced by OATP1A2 (SLCO1A2) . In line with this, Michelon et al. found that MPAG and
AcMPAG, but not MPA, were substrates of OATP1B1.
SLCO1B1
A large number of SLCO1B1 variants have been described. The two SLCO1B1 common variants rs2306283
(p.Asn130Asp, c.388A>G) and rs4149056 (p.Val174Ala, c.521T>C) form together four distinct haplotypes:
SLCO1B1*1A (c.388A-c.521T, reference haplotype), *1B (c.388G-c.521T), *5 (c.388A-c.521C) and *15
[69]
(c.388G-c.521C) .

Kidney transplantation with macrolide or cyclosporine-based treatment has shown no association between
the SLCO1B1 c.388A>G, c.521T>C, and rs11045819 (463C>A) variants or haplotypes with MPA, MPAG or
AcMPAG pharmacokinetics [14,24,49,59,65] .

Likewise, SLCO1B1 variants have not been associated with AR, DGF, diarrhea, leukopenia or neutrophil count
in the studies summarized in Table 2 [22,24,27,49,59,65] . Nevertheless, SLCO1B1 c.521C allele (SLCO1B1*5) was
associated with reduced MPA-related adverse events, including leukopenia, anemia, thrombocytopenia,
diarrhea, nausea, vomiting or infection in French patients on cyclosporine-free treatment . Possibly
[13]