**7. Conclusions**

inconsistent [26, 104, 107, 108]. For more details, readers may refer to [100, 109], one of which

MMF is the most widely used antiproliferative agent [2], after administration, MMF is hydrolyzed to form MPA, which is in turn glucuronidated by several members of the uridine diphosphate-glucuronosyl transferase (UGT) family to form the main metabolite 7-O-MPAglucuronide (MPAG). MPAG is excreted into bile by ABCC2 (or MRP2) and undergoes enterohepatic circulation [100]. Organic anion transporting polypeptides (OATPs, encoded by the SLCO genes), ABCB1 (P-glycoprotein, encoded by the ABCB1 gene), and cytochrome P450

As mentioned above, the UGT family plays an important role in the metabolic process MMF, of which, UGT1A9 is the most important family member that may affect the PK of MPA [110]. Reportedly, there a significant influence of the UGT1A9-2152C>T (rs17868320) and −275T>A (rs6714486) SNPs on MPA PK, while this conclusion seems to depend on the MPA dose, type

Another UGT1A9 SNP, −98T>C (or UGT1A9\*3) has also been found to be associated with higher MPA exposure in healthy volunteers and kidney transplantation recipients [111,

As for the association between MPA PK and genetic variants in UGT1A8 or UGT2B7, reported results remain conflicting. Further investigation is needed to reveal the associations between

ABCC2 is responsible for the biliary and renal excretion of MPAG and is inhibited by CsA [117]. According to the reports, the ABCC2 -24C>T has been studied most extensively among the SNPs that have been identified in the ABCC2 gene [110]. Some studies did find a significant relationship between various ABCC2 SNPs and MPA PK [118, 119], while many other

The OATPs 1B1 (SLCO1B1 gene) and 1B3 (SLCO1B3 gene), 2 uptake transporters located on the sinusoidal side of the hepatocytes, are involved in the uptake of circulating MPAG in

Among the SNPs that have been described in SLCO1B1, the nonsynonymous 521T>C (Val174Ala) and 388A>G (Asn130Asp) SNPs are associated with altered transport activity. These 2 SNPs are in LD and form haplotypes designated as SLCO1B1\*1A (388A-521T),

hepatocytes [112], which contributes to MPA enterohepatic circulation.

was specifically devoted to EVE.

110 Genetic Diversity and Disease Susceptibility

**6.1. UGT1A9 and MPA**

MPA PK and UGT genotype [110, 116].

studies have reported differently [110, 112, 113].

**6.3. SLCO1B1 gene, SLCO1B3 gene, and MPA**

113–115].

**6.2. ABCC2 and MPA**

**6. GP and mycophenolic acid (MPA)**

(CYP) 2C8 and CYP3A4/5 are also involved in the PK of MPA [110].

of concomitant CNI (CsA or Tac), and time after transplantation [111–114].

Tremendous efforts have been made in order to better understand the individual differences of IS. The genetics polymorphisms mentioned above are more or less related to the variability of IS PK/PD. To date, our knowledge of GP associated with IS in SOT is insufficient. It is still not sure whether genotype testing of these alleles would improve clinical outcome of SOT, this technique is definitely effective in depicting the PK parameters of IS, and has the potential to increase the chance of determining the best drug and the correct initial dose. A benefit of genotyping as a predictive test is that this is a fixed characteristic that will not change with pharmacological and physiological status [12]. Algorithms based on multiple genotypes may have a better performance in predicting the required dose, which helps recipients achieve target IS concentration faster with fewer dose adjustments. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has also published Tac dosing guidelines based on CYP3A5 genotype expression [127], which is inspiring that the transplant community devotes such great efforts to the PG research.

[4] Flechner SM, Goldfarb D, Modlin C, et al. Kidney transplantation without calcineurin inhibitor drugs: A prospective, randomized trial of sirolimus versus cyclosporine.

Gene Polymorphisms of Immunosuppressants in Solid Organ Transplantation

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Whatever, based on the present literature, a study of initial tacrolimus dosing based on the CYP3A5 genotype would be logical. And according to [47], the French National Network of Pharmacogenetics (Réseau national de pharmacogénétique [RNPGx]) considered CYP3A4 (CYP3A4\*22) genotyping would be potentially useful.
