Open access peer-reviewed chapter

Gene Polymorphisms of Immunosuppressants in Solid Organ Transplantation

Written By

Yingzi Ming and Meng Yu

Submitted: December 4th, 2017 Reviewed: February 20th, 2018 Published: October 17th, 2018

DOI: 10.5772/intechopen.75717

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Abstract

The rapid development of immunosuppressants (IS) has already improved the prognosis of recipients post solid organ transplantation (SOT) in the past decades. However, the individual difference in IS metabolism may lead to either rejection or drug toxicity, thus suggesting the importance of personalized therapy. Gene polymorphisms (GP) regarding metabolic enzymes and medication transporters of the IS consist the footstone for personalized therapy, which are the hotspots in recent years. However, although a great of efforts have been put into researching the association between GP and pharmacokinetics (PK) or pharmacodynamics (PD), controversial results still remained. The only consensus that has been reached is the use of GP-based IS therapy could help the recipients to reach target concentration faster with less dose adjustment. Whether the GP-based IS therapy could improve the clinical long-term outcome needs further confirmation. In our chapter, we would summarize the information associated with GP of IS, and discuss the potential impact of GP on clinical practice to provide new insights into guiding tailored therapy of IS in SOT.

Keywords

  • gene polymorphisms
  • immunosuppressants
  • solid organ transplantation
  • pharmacokinetics
  • pharmacogenetics

1. Introduction

SOT has prominently reduced mortality and morbidity when facing conditions of end-stage organ failure [1]. To prevent rejection of SOT, the use of IS is essential. And with the continuous development of medical technology, individualized treatment has been paid much more attention. With the advent of new drugs, more choices of IS combination are available in present clinical practice, and the most widely used of which is a calcineurin inhibitor (CNI) + an antiproliferative agent + corticosteroid. Tacrolimus (Tac) and ciclosporin (CsA) are both CNI, and Tac has held most of the market in recent years. Mycophenolate (MMF) is the most widely used antiproliferative agent, which is a prodrug of mycophenolic acid (MPA) that has immunosuppressive activity [2]. There is also a monosodium salt of MPA that was developed to overcome the gastrointestinal side effects of MMF. Ahead of the “triple immunosuppressive therapy”, many maintenance regimens also have induction therapy, which consists of antibodies to lymphocytes. The mammalian target of rapamycin (mTOR) is a more recent IS, which includes sirolimus (SRL) and everolimus (EVE). They were first envisaged as a primary IS in regimens without CNI [1, 3, 4], while now, most of the time they are used at low doses in CNI-sparing regimens [5, 6].

To achieve the target blood concentration fast with less dose adjustment is clinically important, for the therapeutic window of these IS is narrow, which may lead to either acute rejection or over-immunosuppression [7, 8, 9]. There are also numerous drug-specific adverse effects, CNI has a closer relation to high blood pressure hypertension, nephrotoxicity, and new-onset diabetes after transplantation (NODAT) [10], steroids may also lead to NODAT [11], and the mTOR inhibitors are often associated with delayed wound healing and hyperlipidemia [8]. In the majority of cases, these adverse effects are associated with high drug concentrations in the blood, but this is by no means universal [12].

In consideration of inter-individual variation in PK of IS, monitoring the blood concentration has been essential. Therapeutic drug monitoring (TDM) has been widely used to ensure the blood concentration of CNI and SRL [13]. In daily clinical practice, the blood sample is taken and measured at a single time-point immediately before the next dose (called C0 or trough concentration). Although recent studies have suggested that, for measurement of CsA, 2 h after dosing (C2) correlates better with the area under the concentration-time curve (AUC) compared to C0 [9]. This may also apply for Tac, but the practice has not been adopted widely [12, 14, 15].

TDM is no doubt powerful and indispensable in the current management of IS, while many patients may still experience a significant delay in achieving target blood-concentrations, and drug dosage need to be adjusted repeatedly, which could significantly increase the risk of acute graft rejection [9, 16]. The narrow therapeutic window of the IS makes it impossible to use a higher initial dose for all patients, and here comes an unmet need for a strategy, which can lead to the fast achievement of IS target blood concentration in the period immediately following transplantation for all the patients. Fortunately, the investigation of GP combined with critical patient data and concomitant medications may help and thus potentially reduce the adverse events related to over- or under-exposure. In addition, studies may also possibly reveal the association between GP and IS PD, which may help clinicians to choose a better combination of IS for the specific group. A strategy based on GP is most likely to be effective when a single gene has a major influence on the absorption, disposition, elimination or tissue compartmentalization of a drug [12].

This chapter discusses the published genetic associations with IS PK and PD, and their potential use in clinical practice to guide drug dosing in SOT.

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2. GP and Tac

Tac is a 23-membered macrolide lactone isolated from Streptomyces tsukubaensis in 1987 for the first time [17], and in 1994, the US Food and Drug Administration firstly approved Tac for liver transplantation. Due to its excellent efficacy, Tac has been extended as a first-line regimen for kidney, heart, lung, intestinal and bone marrow transplantation. Genetic factors including CYP3A5*3, CYP3A4*1B, CYP3A4*22, ABCB1, and POR*28 have been reported frequently for their influence on Tac dose requirement, which reveals the importance of GP of Tac.

2.1. CYP3A5 and Tac

Reportedly, polymorphisms in the CYP3A5 gene may explain 40–50% of the variability in Tac dose requirement [18, 19]. The hottest SNP studied in CYP3A5 is CYP3A5*3, which is an A to G transition at position 6986 within intron 3 (rs776746) [20]. This mutation leads to alternative splicing, and truncation of the protein, which decreases the function of the CYP3A5 enzyme [21]. As a result, CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3 genotype) have significantly lower dose-adjusted C0 compared to CYP3A5 non-expressers (CYP3A5*3/*3 genotype), and the requirement of Tac dose is CYP3A5*1/*1 > *1/*3 > *3/*3 [20]. A large number of retrospective studies have shown that kidney graft recipients who are CYP3A5 expressers require an approximately 2-fold higher Tac dose compared with non-expressers [22, 23, 24]. In addition, no matter in adult or pediatric heart recipients [25, 26], in lung transplantation recipients [27], as well as in liver transplantation recipients [28], the same relationship has also been observed.

Other CYP3A5 SNPs include CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). CYP3A5*6 encodes a G to A transition at position 14,690, causing a splice variant mRNA and deletion of exon 7, resulting in nonfunctional CYP3A5 protein [21, 29]. CYP3A5*7 denotes a single base insertion at codon 346, causing a frame shift and resulting in a truncated mRNA and nonfunctional CYP3A5 [30].

As for the association between CYP3A5 and the early prediction of the risk of acute rejection, the results are quite inconsistent. Some studies involving Tac therapy did not find any significant association [23, 31, 32, 33, 34], while some other studies reported that CYP3A5 expressers had a higher risk of experiencing biopsy-proven acute rejection (BPAR) [35, 36].

As for other kidney transplantation outcomes involving Tac therapy, such as chronic allograft nephropathy or delayed graft function (DGF). Some studies reported that CYP3A5 expressers had a higher risk of experiencing biopsy-proven Tac-related nephrotoxicity [37, 38] and reduced renal function during the first year after transplantation [36], and CYP3A5 non-expressers were more likely to develop DGF [39] and early renal graft injury as assessed by the urine test [40].

2.2. CYP3A4 and Tac

As for CYP3A4 gene, two SNPs in relation to Tac PK have been investigated extensively: CYP3A4*1B SNP (rs2740574) and CYP3A4*22 SNP (rs35599367).

The CYP3A4*1B SNP involves an A to G transition at position −392 in the promoter region of CYP3A4 and is associated with an increase of CYP3A4 activity [41]. It showed that the C0/D ratio of Tac in patients with the *1B mutation was reduced by 35% compared with that of wild-type homozygotes [42]. However, there is a linkage disequilibrium (LD) between CYP3A4*1B and rs776746 of the CYP3A5 gene. It is possible that the effect of CYP3A4*1B on Tac PK and PD is caused by rs776746, which has been shown in several published studies [43, 44]. Therefore, the exact effect of CYP3A4*1B alone on Tac is still unclear.

The CYP3A4*22 SNP (rs35599367) contains a transition of C to T in intron 6 and is associated with reduced CYP3A4 mRNA expression and CYP3A4 enzyme activity in vitro [45]. In clinic observation of kidney transplantation, the CYP3A4*22 required less Tac dose to achieve the target exposure. What’s more, it was not influenced by the CYP3A5 genotype [46]. However, it should be noted that the frequency of CYP3A4*22 is relatively low. About 5% of the Caucasian population, 3% in the American population, and not found in Asians or Africans [47].

Other CYP3A4 SNPs such as CYP3A4*18 (rs28371759) may also have an impact on Tac PK. This SNP is located in intron 10, with a transition of T to C at position 878. This mutation may increase the activity of the CYP3A4 enzyme and thereby increase the Tac clearance rate and plasma drug concentration [48].

There is also a new and rare CYP3A4 variant, which is now designated as CYP3A4*26. This variant is an 802C>T transition and results in a premature stop codon at position 268 in exon 9 (R268*) [49]. The truncated CYP3A4 protein is non-functional.

When combining CYP3A4 and CYP3A5 genotypes, Elens et al. [50] were able to predict Tac dose requirements better compared with the CYP3A4 or CYP3A5 genotype alone. Based on these observations, it has been proposed to prescribe different Tac doses for ultrarapid (CYP3A5 expressers and CYP3A4 *1/*1), intermediate (CYP3A5 non-expressers and CYP3A4*1/*1) and poor (CYP3A5 non-expressers and CYP3A4*22 carriers) CYP3A metabolizers, respectively [51].

2.3. ABCB1 gene and Tac

P-gp, also known as ABCB1 or MDR1 is a glycoprotein encoded by the human ABCB1 gene, which serves as drug transporter of Tac, and plays an important role in Tac PK. Recently, P-gp has been found to contain more than 50 SNPs. Among them, the ABCB1 3435C>T (rs1045642), 1236C>T (rs1128503) and 2677G>T/A (rs2032582; Ala893Ser/Thr) SNPs have drawn the most attention after intensive investigation [52, 53, 54].

The ABCB1 3435C>T (rs1045642) might be the hottest locus among all the ABCB1 gene SNPs. Reportedly, the frequency of this mutation in orientals is 37–49% [55]. The variation of rs1045642 locus might reduce the expression and function of P-gp in the duodenum, and thus potentially affect the bioavailability of Tac [56].

As for ABCB1 2677G>T/A SNP, wild-type patients required 40% higher Tac dose compared with homozygous carriers of 2677G>T/A SNP (P ≤ 0.05), while the concentration/dose ratio was 36% lower in the wild-type patients (P ≤ 0.02). The haplotype analysis further confirmed the results and suggested that 3435C>T and 2677G>T/A SNPs were associated with daily Tac dose requirements. In addition, the study of these three SNP haploids (1236C>T, 2677G>T/A and 3435C>T, which are in linkage disequilibrium) found that C-G-C (haplotype 1) and T-T/A-T (haplotype 2) accounted for 45.4 and 36.2% of the haplotypes, respectively; individuals with haplotype 1 required significantly higher daily doses of Tac than those with haplotype 2 [57].

Although there are many studies on the association of ABCB1 GP with Tac PK or PD, the results remain inconsistent. To further confirm the association, large-scale genotype-phenotype correlation trials are encouraged.

2.4. POR and Tac

POR is essential for CYP-mediated drug oxidation as an electron donor [58]. POR*28 (rs1057868; A503V) is a coding variant in POR gene, which is believed to be effective in increasing the activity of POR and thus leads to the increasing activities of CYP3A4 and CYP3A5 [59, 60].

it has also been reported frequently that POR*28 carriers have lower adjusted Tac C0 and Tac C0/Tac dose in heart or kidney transplantation, no matter for the adult or the pediatric [61, 62, 63, 64]. Although the strength of this association seems weak and has a limited clinical impact on Tac dose requirements (15–20%), POR*28 may explain a part of Tac variability, and POR*28 carriers may experience faster Tac metabolism [61, 63, 65].

As for the association between POR*28 allele and BPAR after Tac or CsA therapy, no significant evidence was found [63]. As for other graft clinical outcomes, the POR*28 allele was not found to be associated with the higher risk of DGF after Tac therapy in patients with renal transplantation [63]. While it should be noted that one study in recipients with kidney transplantation demonstrated a higher risk of post-transplantation diabetes mellitus (PTDM) in patients carrying the POR*28 allele [60].

2.5. PXR and Tac

As a nuclear transcription, the human pregnane X receptor (PXR), which is encoded by NR1I2, regulates the expression of CYP3A and ABCB1. Polymorphisms of NR1I2 have been reported, but the results regarding their association with Tac dose requirement are conflicting [18, 66, 67].

2.6. PPAR-α and Tac

The expression and activity of CYP3A are also related to the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-α). Two sequence variants in the PPAR-α gene (PPARA), PPARA c.209-1003G>A and c.208+3819A>G, can reduce the PPAR-α expression and contribute to the intra- and inter-individual variability of CYP3A [68]. At present, PPARA c.208+3819A>G appears to have the strongest influence on Tac PK, though it still needs confirmation.

As for graft clinical outcome, one study in kidney transplant recipients demonstrated a higher risk of PTDM who carry the rs4253728 SNP [59].

2.7. Other SNPs and Tac

The multidrug resistance-associated protein 2 (MRP2), which is encoded by the ABCC2, may also be associated with Tac metabolism [69].

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 associated with higher Tac C0/D, but only in CYP3A5 non-expressers. Furthermore, CYP2C8*3 and 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 Tac dose requirements is unknown [73, 74].

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].

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3. GP and CsA

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, 77, 78, 79, 80] or PD [33, 81, 82, 83, 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, no precise dose adjustment has been proposed based on these variants.

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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, 88, 89] and antiviral activity [90, 91, 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 (C0), dose requirement, C0/dose [94, 95]. On the contrary, several other studies described significant associations between SRL exposure and the CYP3A5*3 genotype [96, 97, 98, 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

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 C0/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 C0/dose [96, 98]. In another study, no association was found between SRL C0/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 C0/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, 103, 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.

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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 CNI-sparing 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.

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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-MPA-glucuronide (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, 112, 113, 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, 114, 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].

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7. Conclusions

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.

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.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (no. 81771722) to YZ.M.

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Conflict of interest

No conflict of interest.

References

  1. 1. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. The New England Journal of Medicine. 1999;341:1725-1730. DOI: 10.1056/NEJM199912023412303
  2. 2. van Gelder T, Hesselink DA. Mycophenolate revisited. Transplant International. 2015;28:508-515. DOI: 10.1111/tri.12554
  3. 3. Larson TS, Dean PG, Stegall MD, et al. Complete avoidance of calcineurin inhibitors in renal transplantation: A randomized trial comparing sirolimus and tacrolimus. American Journal of Transplantation. 2006;6:514-522. DOI: 10.1111/j.1600-6143.2005.01177.x
  4. 4. Flechner SM, Goldfarb D, Modlin C, et al. Kidney transplantation without calcineurin inhibitor drugs: A prospective, randomized trial of sirolimus versus cyclosporine. Transplantation. 2002;74:1070-1076. DOI: 10.1097/01.TP.0000037984.17605.B9
  5. 5. Ganschow R, Pollok JM, Jankofsky M, et al. The role of everolimus in liver transplantation. Clinical and Experimental Gastroenterology. 2014;7:329-343. DOI: 10.2147/CEG.S41780
  6. 6. Moes DJ, Guchelaar HJ, de Fijter JW. Sirolimus and everolimus in kidney transplantation. Drug Discovery Today. 2015;20:1243-1249. DOI: 10.1016/j.drudis.2015.05.006
  7. 7. Venkataramanan R, Shaw LM, Sarkozi L, et al. Clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients. Journal of Clinical Pharmacology. 2001;41:542-551
  8. 8. Kahan BD, Napoli KL, Kelly PA, et al. Therapeutic drug monitoring of sirolimus: Correlations with efficacy and toxicity. Clinical Transplantation. 2000;14:97-109
  9. 9. Clase CM, Mahalati K, Kiberd BA, et al. Adequate early cyclosporin exposure is critical to prevent renal allograft rejection: Patients monitored by absorption profiling. American Journal of Transplantation. 2002;2:789-795
  10. 10. Nankivell BJ, Borrows RJ, Fung CL, et al. The natural history of chronic allograft nephropathy. The New England Journal of Medicine. 2003;349:2326-2333. DOI: 10.1056/NEJMoa020009
  11. 11. Davidson JA, Wilkinson A. New-onset diabetes after transplantation 2003 international consensus guidelines: An endocrinologist's view. Diabetes Care. 2004;27:805-812
  12. 12. Ng FL, Holt DW, MacPhee IA. Pharmacogenetics as a tool for optimising drug therapy in solid-organ transplantation. Expert Opinion on Pharmacotherapy. 2007;8:2045-2058. DOI: 10.1517/14656566.8.13.2045
  13. 13. Holt DW. Therapeutic drug monitoring of immunosuppressive drugs in kidney transplantation. Current Opinion in Nephrology and Hypertension. 2002;11:657-663. DOI: 10.1097/01.mnh.0000040053.33359.26
  14. 14. Wong KM, Shek CC, Chau KF, et al. Abbreviated tacrolimus area-under-the-curve monitoring for renal transplant recipients. American Journal of Kidney Diseases. 2000;35:660-666
  15. 15. Scholten EM, Cremers SC, Schoemaker RC, et al. AUC-guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients. Kidney International. 2005;67:2440-2447. DOI: 10.1111/j.1523-1755.2005.00352.x
  16. 16. Undre NA, van Hooff J, Christiaans M, et al. Low systemic exposure to tacrolimus correlates with acute rejection. Transplantation Proceedings. 1999;31:296-298
  17. 17. Pritchard DI. Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discovery Today. 2005;10:688-691. DOI: 10.1016/S1359-6446(05)03395-7
  18. 18. Press RR, Ploeger BA, den Hartigh J, et al. Explaining variability in tacrolimus pharmacokinetics to optimize early exposure in adult kidney transplant recipients. Therapeutic Drug Monitoring. 2009;31:187-197. DOI: 10.1097/FTD.0b013e31819c3d6d
  19. 19. Haufroid V, Mourad M, Van Kerckhove V, et al. The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics. 2004;14:147-154
  20. 20. Hesselink DA, Bouamar R, Elens L, et al. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clinical Pharmacokinetics. 2014;53:123-139. DOI: 10.1007/s40262-013-0120-3
  21. 21. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nature Genetics. 2001;27:383-391. DOI: 10.1038/86882
  22. 22. Tang HL, Xie HG, Yao Y, et al. Lower tacrolimus daily dose requirements and acute rejection rates in the CYP3A5 nonexpressers than expressers. Pharmacogenetics and Genomics. 2011;21:713-720. DOI: 10.1097/FPC.0b013e32834a48ca
  23. 23. Terrazzino S, Quaglia M, Stratta P, et al. The effect of CYP3A5 6986A>G and ABCB1 3435C>T on tacrolimus dose-adjusted trough levels and acute rejection rates in renal transplant patients: A systematic review and meta-analysis. Pharmacogenetics and Genomics. 2012;22:642-645. DOI: 10.1097/FPC.0b013e3283557c74
  24. 24. Birdwell KA, Grady B, Choi L, et al. The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients. Pharmacogenetics and Genomics. 2012;22:32-42. DOI: 10.1097/FPC.0b013e32834e1641
  25. 25. Zheng H, Webber S, Zeevi A, et al. Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. American Journal of Transplantation. 2003;3:477-483
  26. 26. Kniepeiss D, Renner W, Trummer O, et al. The role of CYP3A5 genotypes in dose requirements of tacrolimus and everolimus after heart transplantation. Clinical Transplantation. 2011;25:146-150. DOI: 10.1111/j.1399-0012.2009.01198.x
  27. 27. Zheng H, Zeevi A, Schuetz E, et al. Tacrolimus dosing in adult lung transplant patients is related to cytochrome P4503A5 gene polymorphism. Journal of Clinical Pharmacology. 2004;44:135-140. DOI: 10.1177/0091270003262108
  28. 28. Goto M, Masuda S, Kiuchi T, et al. CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation. Pharmacogenetics. 2004;14:471-478
  29. 29. Santoro A, Felipe CR, Tedesco-Silva H, et al. Pharmacogenetics of calcineurin inhibitors in Brazilian renal transplant patients. Pharmacogenomics. 2011;12:1293-1303. DOI: 10.2217/pgs.11.70
  30. 30. Hustert E, Haberl M, Burk O, et al. The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics. 2001;11:773-779
  31. 31. Hesselink DA, van Schaik RH, van Agteren M, et al. CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipients. Pharmacogenetics and Genomics. 2008;18:339-348. DOI: 10.1097/FPC.0b013e3282f75f88
  32. 32. Satoh S, Saito M, Inoue T, et al. CYP3A5 *1 allele associated with tacrolimus trough concentrations but not subclinical acute rejection or chronic allograft nephropathy in Japanese renal transplant recipients. European Journal of Clinical Pharmacology. 2009;65:473-481. DOI: 10.1007/s00228-008-0606-3
  33. 33. Bouamar R, Hesselink DA, van Schaik RH, et al. Polymorphisms in CYP3A5, CYP3A4, and ABCB1 are not associated with cyclosporine pharmacokinetics nor with cyclosporine clinical end points after renal transplantation. Therapeutic Drug Monitoring. 2011;33:178-184. DOI: 10.1097/FTD.0b013e31820feb8e
  34. 34. Glowacki F, Lionet A, Buob D, et al. CYP3A5 and ABCB1 polymorphisms in donor and recipient: Impact on Tacrolimus dose requirements and clinical outcome after renal transplantation. Nephrology, Dialysis, Transplantation. 2011;26:3046-3050. DOI: 10.1093/ndt/gfr253
  35. 35. Quteineh L, Verstuyft C, Furlan V, et al. Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft recipients. Basic & Clinical Pharmacology & Toxicology. 2008;103:546-552. DOI: 10.1111/j.1742-7843.2008.00327.x
  36. 36. Min SI, Kim SY, Ahn SH, et al. CYP3A5 *1 allele: Impacts on early acute rejection and graft function in tacrolimus-based renal transplant recipients. Transplantation. 2010;90:1394-1400. DOI: 10.1097/TP.0b013e3181fa93a4
  37. 37. Kuypers DR, de Jonge H, Naesens M, et al. CYP3A5 and CYP3A4 but not MDR1 single-nucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxicity in renal recipients. Clinical Pharmacology and Therapeutics. 2007;82:711-725. DOI: 10.1038/sj.clpt.6100216
  38. 38. Kuypers DR, Naesens M, de Jonge H, et al. Tacrolimus dose requirements and CYP3A5 genotype and the development of calcineurin inhibitor-associated nephrotoxicity in renal allograft recipients. Therapeutic Drug Monitoring. 2010;32:394-404. DOI: 10.1097/FTD.0b013e3181e06818
  39. 39. Kuypers DR, de Jonge H, Naesens M, et al. A prospective, open-label, observational clinical cohort study of the association between delayed renal allograft function, tacrolimus exposure, and CYP3A5 genotype in adult recipients. Clinical Therapeutics. 2010;32:2012-2023. DOI: 10.1016/j.clinthera.2010.11.010
  40. 40. Shi Y, Li Y, Tang J, et al. Influence of CYP3A4, CYP3A5 and MDR-1 polymorphisms on tacrolimus pharmacokinetics and early renal dysfunction in liver transplant recipients. Gene. 2013;512:226-231. DOI: 10.1016/j.gene.2012.10.048
  41. 41. Knops N, Levtchenko E, van den Heuvel B, et al. From gut to kidney: Transporting and metabolizing calcineurin-inhibitors in solid organ transplantation. International Journal of Pharmaceutics. 2013;452:14-35. DOI: 10.1016/j.ijpharm.2013.05.033
  42. 42. Hesselink DA, van Schaik RH, van der Heiden IP, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clinical Pharmacology and Therapeutics. 2003;74:245-254. DOI: 10.1016/S0009-9236(03)00168-1
  43. 43. Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. Clinical Pharmacokinetics. 2010;49:141-175. DOI: 10.2165/11317350-000000000-00000
  44. 44. Bandur S, Petrasek J, Hribova P, et al. Haplotypic structure of ABCB1/MDR1 gene modifies the risk of the acute allograft rejection in renal transplant recipients. Transplantation. 2008;86:1206-1213. DOI: 10.1097/TP.0b013e318187c4d1
  45. 45. Wang D, Guo Y, Wrighton SA, et al. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. The Pharmacogenomics Journal. 2011;11:274-286. DOI: 10.1038/tpj.2010.28
  46. 46. Elens L, Bouamar R, Hesselink DA, et al. A new functional CYP3A4 intron 6 polymorphism significantly affects tacrolimus pharmacokinetics in kidney transplant recipients. Clinical Chemistry. 2011;57:1574-1583. DOI: 10.1373/clinchem.2011.165613
  47. 47. Woillard JB, Chouchana L, Picard N, et al. Pharmacogenetics of immunosuppressants: State of the art and clinical implementation—recommendations from the French National Network of Pharmacogenetics (RNPGx). Thérapie. 2017;72:285-299. DOI: 10.1016/j.therap.2016.09.016
  48. 48. Chiu KW, Hu TH, Nakano T, et al. Biological interactions of CYP2C19 genotypes with CYP3A4*18, CYP3A5*3, and MDR1-3435 in living donor liver transplantation recipients. Transplantation Research. 2013;2:6. DOI: 10.1186/2047-1440-2-6
  49. 49. Werk AN, Cascorbi I. Functional gene variants of CYP3A4. Clinical Pharmacology and Therapeutics. 2014;96:340-348. DOI: 10.1038/clpt.2014.129
  50. 50. Elens L, van Schaik RH, Panin N, et al. Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitors' dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenomics. 2011;12:1383-1396. DOI: 10.2217/pgs.11.90
  51. 51. Elens L, Bouamar R, Shuker N, et al. Clinical implementation of pharmacogenetics in kidney transplantation: Calcineurin inhibitors in the starting blocks. British Journal of Clinical Pharmacology. 2014;77:715-728. DOI: 10.1111/bcp.12253
  52. 52. Hoffmeyer S, Burk O, Von RO, et al. Functional polymorphisms of the human multidrug-resistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2000;97:3473-3478. DOI: 10.1073/pnas.050585397
  53. 53. Wang D, Johnson AD, Papp AC, et al. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenetics and Genomics. 2005;15:693-704
  54. 54. Kimchi-Sarfaty C, Oh JM, Kim IW, et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science. 2007;315:525-528. DOI: 10.1126/science.1135308
  55. 55. Chen B, Fang J, Zhang W, et al. Detection of C1236T, G2677T/A, and C3435T polymorphism of MDR1 by amplification refractory mutation system PCR. Journal of Clinical Laboratory Analysis. 2009;23:110-116. DOI: 10.1002/jcla.20299
  56. 56. Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part II. Clinical Pharmacokinetics. 2010;49:207-221. DOI: 10.2165/11317550-000000000-00000
  57. 57. Anglicheau D, Verstuyft C, Laurent-Puig P, et al. Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. Journal of the American Society of Nephrology. 2003;14:1889-1896
  58. 58. Hart SN, Zhong XB. P450 oxidoreductase: Genetic polymorphisms and implications for drug metabolism and toxicity. Expert Opinion on Drug Metabolism & Toxicology. 2008;4:439-452. DOI: 10.1517/17425255.4.4.439
  59. 59. Elens L, Sombogaard F, Hesselink DA, et al. Single-nucleotide polymorphisms in P450 oxidoreductase and peroxisome proliferator-activated receptor-α are associated with the development of new-onset diabetes after transplantation in kidney transplant recipients treated with tacrolimus. Pharmacogenetics and Genomics. 2013;23:649-657
  60. 60. Elens L, Nieuweboer AJ, Clarke SJ, et al. Impact of POR*28 on the clinical pharmacokinetics of CYP3A phenotyping probes midazolam and erythromycin. Pharmacogenetics and Genomics. 2013;23:148-155. DOI: 10.1097/FPC.0b013e32835dc113
  61. 61. Lesche D, Sigurdardottir V, Setoud R, et al. CYP3A5*3 and POR*28 genetic variants influence the required dose of tacrolimus in heart transplant recipients. Therapeutic Drug Monitoring. 2014;36:710-715. DOI: 10.1097/FTD.0000000000000080
  62. 62. de Jonge H, Metalidis C, Naesens M, et al. The P450 oxidoreductase *28 SNP is associated with low initial tacrolimus exposure and increased dose requirements in CYP3A5-expressing renal recipients. Pharmacogenomics. 2011;12:1281-1291. DOI: 10.2217/pgs.11.77
  63. 63. Elens L, Hesselink DA, Bouamar R, et al. Impact of POR*28 on the pharmacokinetics of tacrolimus and cyclosporine A in renal transplant patients. Therapeutic Drug Monitoring. 2014;36:71-79. DOI: 10.1097/FTD.0b013e31829da6dd
  64. 64. Gijsen VM, van Schaik RH, Soldin OP, et al. P450 oxidoreductase *28 (POR*28) and tacrolimus disposition in pediatric kidney transplant recipients—A pilot study. Therapeutic Drug Monitoring. 2014;36:152-158. DOI: 10.1097/FTD.0b013e3182a3f282
  65. 65. Lunde I, Bremer S, Midtvedt K, et al. The influence of CYP3A, PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients. European Journal of Clinical Pharmacology. 2014;70:685-693. DOI: 10.1007/s00228-014-1656-3
  66. 66. Benkali K, Prémaud A, Picard N, et al. Tacrolimus population pharmacokinetic-pharmacogenetic analysis and Bayesian estimation in renal transplant recipients. Clinical Pharmacokinetics. 2009;48:805-816. DOI: 10.2165/11318080-000000000-00000
  67. 67. Barraclough KA, Isbel NM, Lee KJ, et al. NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation. Transplantation. 2012;94:1025-1032. DOI: 10.1097/TP.0b013e31826c3985
  68. 68. Klein K, Thomas M, Winter S, et al. PPARA: A novel genetic determinant of CYP3A4 in vitro and in vivo. Clinical Pharmacology and Therapeutics. 2012;91:1044-1052. DOI: 10.1038/clpt.2011.336
  69. 69. Ogasawara K, Chitnis SD, Gohh RY, et al. Multidrug resistance-associated protein 2 (MRP2/ABCC2) haplotypes significantly affect the pharmacokinetics of tacrolimus in kidney transplant recipients. Clinical Pharmacokinetics. 2013;52:751-762. DOI: 10.1007/s40262-013-0069-2
  70. 70. Aquilante CL, Niemi M, Gong L, et al. PharmGKB summary: Very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 8. Pharmacogenetics and Genomics. 2013;23:721-728. DOI: 10.1097/FPC.0b013e3283653b27
  71. 71. Suarez-Kurtz G, Pena SD, Struchiner CJ, et al. Pharmacogenomic diversity among Brazilians: Influence of ancestry, self-reported color, and geographical origin. Frontiers in Pharmacology. 2012;3:191. DOI: 10.3389/fphar.2012.00191
  72. 72. Genvigir FDV, Nishikawa AM, Felipe CR, et al. Influence of ABCC2, CYP2C8, and CYP2J2 polymorphisms on Tacrolimus and Mycophenolate sodium-based treatment in Brazilian kidney transplant recipients. Pharmacotherapy. 2017;37:511-514. DOI: 10.1002/phar.1928
  73. 73. Fan J, Zhang X, Ren L, et al. Donor IL-18 rs5744247 polymorphism as a new biomarker of tacrolimus elimination in Chinese liver transplant patients during the early post-transplantation period: Results from two cohort studies. Pharmacogenomics. 2015;16:239-250. DOI: 10.2217/pgs.14.166
  74. 74. Zhang X, Wang Z, Fan J, et al. Impact of interleukin-10 gene polymorphisms on tacrolimus dosing requirements in Chinese liver transplant patients during the early posttransplantation period. European Journal of Clinical Pharmacology. 2011;67:803-813. DOI: 10.1007/s00228-011-0993-8
  75. 75. Liu MZ, He HY, Zhang YL, et al. IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients. Acta Pharmacologica Sinica. 2017;38:415-423. DOI: 10.1038/aps.2016.153
  76. 76. Anglicheau D, Thervet E, Etienne I, et al. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clinical Pharmacology and Therapeutics. 2004;75:422-433. DOI: 10.1016/j.clpt.2004.01.009
  77. 77. Von AN, Richter M, Grupp C, et al. No influence of the MDR-1 C3435T polymorphism or a CYP3A4 promoter polymorphism (CYP3A4-V allele) on dose-adjusted cyclosporin A trough concentrations or rejection incidence in stable renal transplant recipients. Clinical Chemistry. 2001;47:1048-1052
  78. 78. de Jonge H, Vanhove T, de Loor H, et al. Progressive decline in tacrolimus clearance after renal transplantation is partially explained by decreasing CYP3A4 activity and increasing haematocrit. British Journal of Clinical Pharmacology. 2015;80:548-559. DOI: 10.1111/bcp.12703
  79. 79. Crettol S, Venetz JP, Fontana M, et al. CYP3A7, CYP3A5, CYP3A4, and ABCB1 genetic polymorphisms, cyclosporine concentration, and dose requirement in transplant recipients. Therapeutic Drug Monitoring. 2008;30:689-699. DOI: 10.1097/FTD.0b013e31818a2a60
  80. 80. Hesselink DA, van Gelder T, van Schaik RH, et al. Population pharmacokinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic polymorphisms in the MDR-1, CYP3A4, and CYP3A5 genes. Clinical Pharmacology and Therapeutics. 2004;76:545-556. DOI: 10.1016/j.clpt.2004.08.022
  81. 81. Elens L, Bouamar R, Hesselink DA, et al. The new CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with an increased risk of delayed graft function and worse renal function in cyclosporine-treated kidney transplant patients. Pharmacogenetics and Genomics. 2012;22:373-380. DOI: 10.1097/FPC.0b013e328351f3c1
  82. 82. Bouamar R, Hesselink DA, van Schaik RH, et al. Mycophenolic acid-related diarrhea is not associated with polymorphisms in SLCO1B nor with ABCB1 in renal transplant recipients. Pharmacogenetics and Genomics. 2012;22:399-407. DOI: 10.1097/FPC.0b013e32834a8650
  83. 83. Woillard JB, Rerolle JP, Picard N, et al. Donor P-gp polymorphisms strongly influence renal function and graft loss in a cohort of renal transplant recipients on cyclosporine therapy in a long-term follow-up. Clinical Pharmacology and Therapeutics. 2010;88:95-100. DOI: 10.1038/clpt.2010.62
  84. 84. Kreutz R, Bolbrinker J, van der Sman-de Beer F, et al. CYP3A5 genotype is associated with longer patient survival after kidney transplantation and long-term treatment with cyclosporine. The Pharmacogenomics Journal. 2008;8:416-422. DOI: 10.1038/sj.tpj.6500488
  85. 85. Halloran PF. Sirolimus and cyclosporin for renal transplantation. Lancet. 2000;356:179-180
  86. 86. Sehgal SN. Sirolimus: Its discovery, biological properties, and mechanism of action. Transplantation Proceedings. 2003;35:7S-14S
  87. 87. Boratyńska M, Watorek E, Smolska D, et al. Anticancer effect of sirolimus in renal allograft recipients with de novo malignancies. Transplantation Proceedings. 2007;39:2736-2739. DOI: 10.1016/j.transproceed.2007.08.078
  88. 88. Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. The New England Journal of Medicine. 2012;367:329-339. DOI: 10.1056/NEJMoa1204166
  89. 89. Campbell SB, Walker R, Tai SS, et al. Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer. American Journal of Transplantation. 2012;12:1146-1156. DOI: 10.1111/j.1600-6143.2012.04004.x
  90. 90. Havenith SH, Yong SL, Van Donselaar-van der Pant KA, et al. Everolimus-treated renal transplant recipients have a more robust CMV-specific CD8+ T-cell response compared with cyclosporine- or mycophenolate-treated patients. Transplantation. 2013;95:184-191. DOI: 10.1097/TP.0b013e318276a1ef
  91. 91. Kawahara T, Asthana S, Kneteman NM. M-TOR inhibitors: What role in liver transplantation. Journal of Hepatology. 2011;55:1441-1451. DOI: 10.1016/j.jhep.2011.06.015
  92. 92. Liacini A, Seamone ME, Muruve DA, et al. Anti-BK virus mechanisms of sirolimus and leflunomide alone and in combination: Toward a new therapy for BK virus infection. Transplantation. 2010;90:1450-1457. DOI: 10.1097/TP.0b013e3182007be2
  93. 93. Stallone G, Infante B, Grandaliano G, et al. Management of side effects of sirolimus therapy. Transplantation. 2009;87:S23-S26. DOI: 10.1097/TP.0b013e3181a05b7a
  94. 94. Mourad M, Mourad G, Wallemacq P, et al. Sirolimus and tacrolimus trough concentrations and dose requirements after kidney transplantation in relation to CYP3A5 and MDR1 polymorphisms and steroids. Transplantation. 2005;80:977-984
  95. 95. Żochowska D, Wyzgał J, Pączek L. Impact of CYP3A4*1B and CYP3A5*3 polymorphisms on the pharmacokinetics of cyclosporine and sirolimus in renal transplant recipients. Annals of Transplantation. 2012;17:36-44
  96. 96. Anglicheau D, Le CD, Lechaton S, et al. Consequences of genetic polymorphisms for sirolimus requirements after renal transplant in patients on primary sirolimus therapy. American Journal of Transplantation. 2005;5:595-603. DOI: 10.1111/j.1600-6143.2005.00745.x
  97. 97. Le MY, Djebli N, Szelag JC, et al. CYP3A5*3 influences sirolimus oral clearance in de novo and stable renal transplant recipients. Clinical Pharmacology and Therapeutics. 2006;80:51-60. DOI: 10.1016/j.clpt.2006.03.012
  98. 98. Miao LY, Huang CR, Hou JQ, et al. Association study of ABCB1 and CYP3A5 gene polymorphisms with sirolimus trough concentration and dose requirements in Chinese renal transplant recipients. Biopharmaceutics & Drug Disposition. 2008;29:1-5. DOI: 10.1002/bdd.577
  99. 99. Lee J, Huang H, Chen Y, et al. ABCB1 haplotype influences the sirolimus dose requirements in Chinese renal transplant recipients. Biopharmaceutics & Drug Disposition. 2014;35:164-172. DOI: 10.1002/bdd.1881
  100. 100. Picard N, Bergan S, Marquet P, et al. Pharmacogenetic biomarkers predictive of the pharmacokinetics and pharmacodynamics of immunosuppressive drugs. Therapeutic Drug Monitoring. 2016;38(Suppl 1):S57-S69. DOI: 10.1097/FTD.0000000000000255
  101. 101. Woillard JB, Kamar N, Coste S, et al. Effect of CYP3A4*22, POR*28, and PPARA rs4253728 on sirolimus in vitro metabolism and trough concentrations in kidney transplant recipients. Clinical Chemistry. 2013;59:1761-1769. DOI: 10.1373/clinchem.2013.204990
  102. 102. Jacobsen W, Serkova N, Hausen B, et al. Comparison of the in vitro metabolism of the macrolide immunosuppressants sirolimus and RAD. Transplantation Proceedings. 2001;33:514-515
  103. 103. Picard N, Djebli N, Sauvage FL, et al. Metabolism of sirolimus in the presence or absence of cyclosporine by genotyped human liver microsomes and recombinant cytochromes P450 3A4 and 3A5. Drug Metabolism and Disposition. 2007;35:350-355. DOI: 10.1124/dmd.106.012161
  104. 104. Picard N, Rouguieg-Malki K, Kamar N, et al. CYP3A5 genotype does not influence everolimus in vitro metabolism and clinical pharmacokinetics in renal transplant recipients. Transplantation. 2011;91:652-656. DOI: 10.1097/TP.0b013e31820ae4ac
  105. 105. Sam WJ, Chamberlain CE, Lee SJ, et al. Associations of ABCB1 3435C>T and IL-10-1082G>A polymorphisms with long-term sirolimus dose requirements in renal transplant patients. Transplantation. 2011;92:1342-1347. DOI: 10.1097/TP.0b013e3182384ae2
  106. 106. Woillard JB, Kamar N, Rousseau A, et al. Association of sirolimus adverse effects with m-TOR, p70S6K or raptor polymorphisms in kidney transplant recipients. Pharmacogenetics and Genomics. 2012;22:725-732. DOI: 10.1097/FPC.0b013e328357359d
  107. 107. Schoeppler KE, Aquilante CL, Kiser TH, et al. The impact of genetic polymorphisms, diltiazem, and demographic variables on everolimus trough concentrations in lung transplant recipients. Clinical Transplantation. 2014;28:590-597. DOI: 10.1111/ctr.12350
  108. 108. Diekstra MH, Fritsch A, Kanefendt F, et al. Population modeling integrating pharmacokinetics, pharmacodynamics, pharmacogenetics, and clinical outcome in patients with Sunitinib-treated cancer. CPT: Pharmacometrics & Systems Pharmacology. 2017;6:604-613. DOI: 10.1002/psp4.12210
  109. 109. Shipkova M, Hesselink DA, Holt DW, et al. Therapeutic drug monitoring of everolimus: A consensus report. Therapeutic Drug Monitoring. 2016;38:143-169. DOI: 10.1097/FTD.0000000000000260
  110. 110. Barraclough KA, Lee KJ, Staatz CE. Pharmacogenetic influences on mycophenolate therapy. Pharmacogenomics. 2010;11:369-390. DOI: 10.2217/pgs.10.9
  111. 111. Kuypers DR, Naesens M, Vermeire S, et al. The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients. Clinical Pharmacology and Therapeutics. 2005;78:351-361. DOI: 10.1016/j.clpt.2005.06.007
  112. 112. Picard N, Yee SW, Woillard JB, et al. The role of organic anion-transporting polypeptides and their common genetic variants in mycophenolic acid pharmacokinetics. Clinical Pharmacology and Therapeutics. 2010;87:100-108. DOI: 10.1038/clpt.2009.205
  113. 113. van Schaik RH, van Agteren M, de Fijter JW, et al. UGT1A9 -275T>A/-2152C>T polymorphisms correlate with low MPA exposure and acute rejection in MMF/tacrolimus-treated kidney transplant patients. Clinical Pharmacology and Therapeutics. 2009;86:319-327. DOI: 10.1038/clpt.2009.83
  114. 114. Johnson LA, Oetting WS, Basu S, et al. Pharmacogenetic effect of the UGT polymorphisms on mycophenolate is modified by calcineurin inhibitors. European Journal of Clinical Pharmacology. 2008;64:1047-1056. DOI: 10.1007/s00228-008-0501-y
  115. 115. Lévesque E, Delage R, Benoit-Biancamano MO, et al. The impact of UGT1A8, UGT1A9, and UGT2B7 genetic polymorphisms on the pharmacokinetic profile of mycophenolic acid after a single oral dose in healthy volunteers. Clinical Pharmacology and Therapeutics. 2007;81:392-400. DOI: 10.1038/sj.clpt.6100073
  116. 116. Dupuis R, Yuen A, Innocenti F. The influence of UGT polymorphisms as biomarkers in solid organ transplantation. Clinica Chimica Acta. 2012;413:1318-1325. DOI: 10.1016/j.cca.2012.01.031
  117. 117. Hesselink DA, van Hest RM, Mathot RA, et al. Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. American Journal of Transplantation. 2005;5:987-994. DOI: 10.1046/j.1600-6143.2005.00779.x
  118. 118. Naesens M, Kuypers DR, Verbeke K, et al. Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation. 2006;82:1074-1084. DOI: 10.1097/01.tp.0000235533.29300.e7
  119. 119. Lloberas N, Torras J, Cruzado JM, et al. Influence of MRP2 on MPA pharmacokinetics in renal transplant recipients-results of the Pharmacogenomic Substudy within the symphony study. Nephrology, Dialysis, Transplantation. 2011;26:3784-3793. DOI: 10.1093/ndt/gfr130
  120. 120. Niemi M. Role of OATP transporters in the disposition of drugs. Pharmacogenomics. 2007;8:787-802. DOI: 10.2217/14622416.8.7.787
  121. 121. Miura M, Satoh S, Inoue K, et al. Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. European Journal of Clinical Pharmacology. 2007;63:1161-1169. DOI: 10.1007/s00228-007-0380-7
  122. 122. Miura M, Kagaya H, Satoh S, et al. Influence of drug transporters and UGT polymorphisms on pharmacokinetics of phenolic glucuronide metabolite of mycophenolic acid in Japanese renal transplant recipients. Therapeutic Drug Monitoring. 2008;30:559-564. DOI: 10.1097/FTD.0b013e3181838063
  123. 123. Natsumeda Y, Ohno S, Kawasaki H, et al. Two distinct cDNAs for human IMP dehydrogenase. The Journal of Biological Chemistry. 1990;265:5292-5295
  124. 124. Wu TY, Peng Y, Pelleymounter LL, et al. Pharmacogenetics of the mycophenolic acid targets inosine monophosphate dehydrogenases IMPDH1 and IMPDH2: Gene sequence variation and functional genomics. British Journal of Pharmacology. 2010;161:1584-1598. DOI: 10.1111/j.1476-5381.2010.00987.x
  125. 125. Gensburger O, Van Schaik RH, Picard N, et al. Polymorphisms in type I and II inosine monophosphate dehydrogenase genes and association with clinical outcome in patients on mycophenolate mofetil. Pharmacogenetics and Genomics. 2010;20:537-543. DOI: 10.1097/FPC.0b013e32833d8cf5
  126. 126. Sombogaard F, van Schaik RH, Mathot RA, et al. Interpatient variability in IMPDH activity in MMF-treated renal transplant patients is correlated with IMPDH type II 3757T > C polymorphism. Pharmacogenetics and Genomics. 2009;19:626-634. DOI: 10.1097/FPC.0b013e32832f5f1b
  127. 127. Birdwell KA, Decker B, Barbarino JM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clinical Pharmacology and Therapeutics. 2015;98:19-24. DOI: 10.1002/cpt.113

Written By

Yingzi Ming and Meng Yu

Submitted: December 4th, 2017 Reviewed: February 20th, 2018 Published: October 17th, 2018