**5. GP and EVE**

EVE is the hydroxyethyl derivative of SRL, with a similar mechanism of action but much more predictable PK. Clinical trials using EVE followed, first in combination with CNI then in CNIsparing regimens [100].

Again, the reported data about the association between SNP polymorphisms (including CYP3A5\*3, CYP3A4\*22, ABCB1 c.3435C>T, CYP2C8 and PXR) and the PK/PD of EVE are inconsistent [26, 104, 107, 108]. For more details, readers may refer to [100, 109], one of which was specifically devoted to EVE.

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], sug-

Gene Polymorphisms of Immunosuppressants in Solid Organ Transplantation

http://dx.doi.org/10.5772/intechopen.75717

111

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

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 inef-

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

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

gesting a decreased hepatic uptake of the metabolite.

MMF + CsA, no significant effect was observed [112].

type, also explained by accelerated degradation [124].

fective on enzyme activity [124, 125].

**7. Conclusions**

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