CYP3A5 and ABCB1 polymorphisms in donor and recipient: impact on Tacrolimus dose requirements and clinical outcome after renal transplantation

Glowacki, François; Lionet, Arnaud; Buob, David; Labalette, Myriam; Allorge, Delphine; François, Patrice; Hazzan, Marc; Noël, Christian; Broly, Franck; Cauffiez, Christelle

doi:10.1093/ndt/gfr253

Cited by 76 publications

(75 citation statements)

References 12 publications

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“…This is in accordance with the previous assumption that a constantly high dose of Tac may lead to a worsening of renal function. This finding may be contradictory to the majority of previously published studies, but the majority of them limited their observations at the first year after transplantation (6,31). However, certain authors found an association between Tac toxicity and patient genotype.…”

Section: Discussioncontrasting

confidence: 61%

“…The controversy in the results concerning the long-term adverse effects of Tac prompted an assessment of the contribution of CYP 3A5 and ABCB1 polymorphisms on renal function parameters in transplant recipients in the present study. The majority of the previous studies found no correlation between investigated polymorphisms and the clinical features of Tac toxicity or renal function attenuation (6,8,31). The bivariate linear regression showed that CYP 3A5 polymorphism, but not ABCB1 polymorphism, independently affects renal function from 6 to 24 months after renal transplantation (Table V).…”

Section: Discussionmentioning

confidence: 91%

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Investigation of CYP 3A5 and ABCB1 gene polymorphisms in the long-term following renal transplantation: Effects on tacrolimus exposure and kidney function

Stefanović

Cvetković

Jevtović-Stoimenov

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The clinical use of tacrolimus (Tac) is complicated by the large inter-individual variability in its pharmacokinetics as well as by chronic adverse effects on renal function. The main goal of this study was to evaluate the potential influence of cytochrome P450 3A5 (CYP 3A5) and ATP-binding cassette transporter B1 (ABCB1) gene polymorphisms on Tac dose requirements and dose-adjusted concentrations in different long-term periods following renal transplantation. Another aim was to investigate whether these polymorphisms affect renal function in late post-transplant period. A total of 91 renal transplant recipients were enrolled for genotyping analysis, and 53 of these entered into a pharmacokinetic-pharmacogenetic study. Allele-specific polymerase chain reaction was used for CYP 3A5 and ABCB1 polymorphism determination. Pharmacokinetic data (dose, trough concentration and dose-adjusted concentration of Tac) and renal function parameters [creatinine (Cre) clearance and serum Cre level] were analyzed in relation to patient genotype at 6, 12 and 24 months after transplantation. Also, linear regression analysis was performed to evaluate the effect of CYP 3A5 and ABCB1 genotypes on Tac exposure and renal function up to 24 months post-transplant. Individuals carrying the CYP 3A5

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Section: Discussioncontrasting

confidence: 61%

Section: Discussionmentioning

confidence: 91%

Investigation of CYP 3A5 and ABCB1 gene polymorphisms in the long-term following renal transplantation: Effects on tacrolimus exposure and kidney function

Stefanović

Cvetković

Jevtović-Stoimenov

et al. 2015

Experimental and Therapeutic Medicine

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“…[17] Other investigators have also reported that CYP3A5 expressers do not have a higher risk of developing acute rejection. [18][19][20][21][22][23][24][25][26] Although numerous studies have reported the higher Tac dose requirement of CYP3A5 expressers compared to nonexpressers, the clinical relevance of this association is unclear and has so far only been investigated in two randomized-controlled clinical trials (RCT). The Tactique study [27] was a multicenter RCT, including 280 renal transplant recipients.…”

Section: Genetic Variation and Tac Pharmacokineticsmentioning

confidence: 99%

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

Tang

Andrews

Gelder

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

117

114

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Introduction: Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression. Areas covered: The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations. Expert opinion: The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a~40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.ARTICLE HISTORY

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“…A polymorphism in intron 3 of CYP3A5, the CYP3A5*3 allele, results in a premature stop codon, whereas individuals carrying the CYP3A5*1 allele express this enzyme normally . Several studies have associated the presence of CYP3A5*1 allele with lower doseadjusted tacrolimus blood concentrations and higher tacrolimus dose requirements (Glowacki et al, 2011;Cho et al, 2012). On the other hand, the influence of ABCB1 polymorphisms (gene coding for P glycoprotein) on tacrolimus pharmacokinetics and clinical outcomes is still controversial Glowacki et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Increased Hospital Stay and Allograft Disfunction in Renal Transplant Recipients with Cyp2c19 AA Variant in SNP rs4244285

et al. 2012

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Pharmacogenetics correlates certain genetic variants, such as single nucleotide polymorphisms (SNPs), with blood drug levels, efficacy, and adverse effects of the treatment. Tacrolimus is mainly metabolized via CYP3A4/5, whereas CYP2C19 and CYP3A4/5 are responsible for omeprazole metabolism. Omeprazole inhibits tacrolimus metabolism via CYP3A5 in patients carrying variant alleles of CYP2C19, increasing tacrolimus blood concentrations. Seventyfive renal transplant recipients treated with tacrolimus and concomitant omeprazole were genotyped in a panel of 37 SNPs with use of Sequenom MassArray. The patients with CYP2C19*2/*2 genotype (n = 4) showed a median posttransplantation hospital stay of 27.5 days (95% confidence interval [CI], 23-39 days), compared with 12 days (95% CI, 10-15 days) in patients with CYP2C19*1/*1 or CYP2C19*1/*2 (n = 71; P = 0.016, Kruskal-Wallis test).The difference in hospital stay was directly correlated with an increase in tacrolimus levels (C min /[dose/weight]) during the first week after trasplantation (in 59 patients with data on levels; P = 0.021, Kruskal-Wallis), excluding the patients with atypical metabolisms due to

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CYP3A5 and ABCB1 polymorphisms in donor and recipient: impact on Tacrolimus dose requirements and clinical outcome after renal transplantation

Abstract: Recipient CYP3A5 6986A>G polymorphism explains part of the interindividual variability of the pharmacokinetics of Tacrolimus. The clinical outcome at 2-year follow-up does not appear to be related to the donor or recipient CYP3A5 6986A>G and/or ABCB1 3435C>T polymorphisms.

Cited by 76 publications

References 12 publications

Investigation of CYP 3A5 and ABCB1 gene polymorphisms in the long-term following renal transplantation: Effects on tacrolimus exposure and kidney function

Investigation of CYP 3A5 and ABCB1 gene polymorphisms in the long-term following renal transplantation: Effects on tacrolimus exposure and kidney function

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

Increased Hospital Stay and Allograft Disfunction in Renal Transplant Recipients with Cyp2c19 AA Variant in SNP rs4244285

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