**4. GP and SRL**

Both SRL and EVE are the mammalian target of rapamycin inhibitors (mTORi). SRL was not used as IS until the late 1990s. SRL can form a complex with the tacrolimus-binding protein (FKBP), which binds to mTOR. It inhibits the entry of cells from G1 phase to S phase and inhibits T lymphocyte activation (proliferation) [85, 86].

Despite the potential advantages of sirolimus, such as antitumor activity [87–89] and antiviral activity [90–92], there are also a number of side-effects that result in a limit use of mTORi in clinical trials and practice, including PTDM, hyperlipidemia, anemia, proteinuria, oral ulcers, diarrhea, impaired wound healing, interstitial pneumonitis and edema [93].

#### **4.1. CYP3A5 and SRL**

At least 2 studies found no association between the CYP3A5\*3 allele and SRL trough levels (C<sup>0</sup> ), dose requirement, C<sup>0</sup> /dose [94, 95]. On the contrary, several other studies described significant associations between SRL exposure and the CYP3A5\*3 genotype [96–99]. The difference between the two kinds of results may be caused by the co-treated use of CNI. The effect of CYP3A5\*3 genotype on SRL may only be notable in the patients taking no CNI [100].

#### **4.2. CYP3A4 and SRL**

**2.7. Other SNPs and Tac**

108 Genetic Diversity and Disease Susceptibility

ated with higher Tac C<sup>0</sup>

**3. GP and CsA**

**4. GP and SRL**

**4.1. CYP3A5 and SRL**

), dose requirement, C<sup>0</sup>

(C<sup>0</sup>

also be associated with Tac metabolism [69].

Tac dose requirements is unknown [73, 74].

The multidrug resistance-associated protein 2 (MRP2), which is encoded by the ABCC2, may

The CYP2C8 enzyme, which is highly expressed in the liver, can also be found in extrahepatic tissues like kidney [70]. Reported by Suarez-Kurtz et al. [71], the CYP2C8\*3 was associ-

CYP2J2 -76G>T SNPs were reported to influence the renal function of the patients and the occurrence of adverse events during treatment with Tac and mycophenolate sodium [72].

Genetic polymorphisms in IL-18 (e.g., rs5744247) and IL-10 (e.g., −819 C/T and −592 C/A) can also affect Tac dose requirements [50, 62]. However, the exact mechanism by which they affect

Recently, it was also reported that IL-3 rs181781 and CTLA4 rs4553808 genetic polymorphisms probably influence the Tac dose requirements in Chinese kidney transplant recipients [75].

Both CsA and Tac are CNI. The GP that closely related to Tac as mentioned above could have more or less the effect on CsA, and as it should be, the effect is not exactly the same. In recent years, Tac gradually replaces the use of CsA, and here we will not make an in-depth introduction. Reportedly, the influence of the CYP3A5\*3 and CYP3A4\*22 variants on the PK [19, 42, 50, 76–80] or PD [33, 81–84] of CsA are controversial. The effect of CYP3A5\*3 on the CsA PK appears to be weaker than observed for TAC, while the CYP3A4\*22 allele appears to be stronger, which would decrease the clearance of CsA by 15%. As stated in [47], for the time being,

Both SRL and EVE are the mammalian target of rapamycin inhibitors (mTORi). SRL was not used as IS until the late 1990s. SRL can form a complex with the tacrolimus-binding protein (FKBP), which binds to mTOR. It inhibits the entry of cells from G1 phase to S phase and

Despite the potential advantages of sirolimus, such as antitumor activity [87–89] and antiviral activity [90–92], there are also a number of side-effects that result in a limit use of mTORi in clinical trials and practice, including PTDM, hyperlipidemia, anemia, proteinuria, oral ulcers,

At least 2 studies found no association between the CYP3A5\*3 allele and SRL trough levels

/dose [94, 95]. On the contrary, several other studies described

no precise dose adjustment has been proposed based on these variants.

diarrhea, impaired wound healing, interstitial pneumonitis and edema [93].

inhibits T lymphocyte activation (proliferation) [85, 86].

/D, but only in CYP3A5 non-expressers. Furthermore, CYP2C8\*3 and

The CYP3A4\*22 allele was found to be associated with a moderately lower SRL hepatic metabolism in vitro, which, is inconsistent with another study [101]. A 113 stable recipients post renal transplantation switched from a CNI to SRL and found no significant association between this allele and SRL PK.

As for CYP3A4\*1B allele and SRL PK, a study including 149 recipients with renal transplantation confirmed a significant association between this allele and SRL C<sup>0</sup> /dose in the subgroup of 69 patients taking no CNI [96, 97], as the same case in CYP3A5\*3. However, another study reported differently [97].

#### **4.3. ABCB1 and SRL**

As for ABCB1 gene, two studies showed no significant association between the ABCB1 c.3435C>T SNP and the SRL C<sup>0</sup> /dose [96, 98]. In another study, no association was found between SRL C<sup>0</sup> /dose and any of the ABCB1 exon 12, exon 21, and exon 26 SNPs, nor with their haplotype [94].

On the other hand, some reported that ABCB1 haplotype combination has a significant influence on SRL PK [44]. According to the report, the mean SRL C<sup>0</sup> /dose was approximately 30% lower in Chinese renal transplantation recipients carrying ABCB1 CGC/CGC as than those carrying the CGC/TTT or TTT/TTT combinations (no effect of ABCB1 individual SNPs was found).

#### **4.4. Other SNPs and SRL**

As for the POR\*28 allele, the PPARA rs4253728 SNP, and CYP2C8\*3, no significant association was found between these SNPs and SRL PK [60, 68, 102–104].

Reported data about the influence of P450 or ABCB1 gene variants on the PK/PD of SRL are inconsistent [96, 97, 101, 105, 106]. CYP3A5\*3 genotyping might be potentially useful in kidney transplant recipients with no CNI because of the possible competition for CYP3A5 metabolism [100]. As was stated in [47], at the present time, data are insufficient to recommend any genotype test for this immunosuppressant.
