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

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

### **6.1. UGT1A9 and MPA**

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

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, 113–115].

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 MPA PK and UGT genotype [110, 116].

#### **6.2. ABCC2 and MPA**

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

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

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

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), SLCO1B1\*1B (388G-521T), SLCO1B1\*5 (388A-521C), and SLCO1B1\*15 (388G-521C) [120]. In the studies of [112, 121], no significant association was found between the SLCO1B1 SNPs or haplotypes and MPA PK in renal transplantation recipients. In another study, SLCO1B1\*15 allele carriers are found to be related to a lower level of MPAG than in noncarriers [122], suggesting a decreased hepatic uptake of the metabolite.

As for the various of SNPs in SLCO1B3, the most frequent are a T>G substitution at position 334 and a G>A substitution at position 699 (in complete LD), which result in 2 amino acid changes (Ser112Ala and Met233Ile). In a study of renal transplant recipients receiving MMF with no CsA immunosuppressive regimen, the SLCO1B3 334G allele was found to be associated with a significantly lower MPA dose-normalized exposure, Whereas in the group of MMF + CsA, no significant effect was observed [112].

#### **6.4. Inosine monophosphate dehydrogenase (IMPDH) and MPA**

The mechanism of action of MPA is the inhibition of the rate-limiting enzyme in de novo purine synthesis, inosine monophosphate dehydrogenase (IMPDH). Followed by the characterization of 2 isoforms in humans, IMPDH1 and IMPDH2 [123], many other genetic variants of both isoforms have been identified. Although a few of them seem to have an effect on the expression or the enzyme activity directly, most of the genetic variants are either rare or ineffective on enzyme activity [124, 125].

As for the potential influence of IMPDH variants on IMPDH activity, a study in a group of renal transplantation recipients on MPA demonstrated that the enzyme activity over 12 h was 49% higher in patients with the IMPDH2 variant rs11706052 than in patients with the wild-type. While in the group with no MPA, no difference was found [126]. In addition, for the IMPDH2 variant rs121434586, which has only been reported at a very low frequency, the enzyme activity is reduced to approximately 21% of wild-type activity, probably because of accelerated protein degradation. For the IMPDH1 variant only found in the Han Chinese-American group (rs72624960), the enzyme activity is as low as 10% compared with the wild type, also explained by accelerated degradation [124].
