Effect of CYP3A5*1/*3 Polymorphism on Blood Pressure in Renal Transplant Recipients

Torı́o, Alberto; Auyanet, Ingrid; Montes-Ares, Olga; Guerra, Rita; Fernández, Ephrem; Pérez, M.A.; Ramiréz, Agustín J.; Checa, María Dolores

doi:10.1016/j.transproceed.2012.09.047

Cited by 6 publications

(3 citation statements)

References 11 publications

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“… 45 In a study of renal transplant recipients, the CYP3A5 *1 allele carriers likewise had higher adjusted systolic and diastolic blood pressure at 6 months and 24 months posttransplant compared to noncarriers, although the difference was not statistically significant. 53 There was also a trend for a higher number of antihypertensives used among the CYP3A5 *1 allele carriers, although this was not statistically significant either.…”

Section: Which Genotype Is Relevant: Recipient or Donor?mentioning

confidence: 83%

CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment

Chen¹,

Prasad²

2018

PGPM

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Tacrolimus is a commonly used immunosuppressant after kidney transplantation. It has a narrow therapeutic range and demonstrates wide interindividual variability in pharmacokinetics, leading to potential underimmunosuppression or toxicity. Genetic polymorphism in CYP3A5 enzyme expression contributes to differences in tacrolimus bioavailability between individuals. Individuals carrying one or more copies of the wild-type allele *1 express CYP3A5, which increases tacrolimus clearance. CYP3A5 expressers require 1.5 to 2-fold higher tacrolimus doses compared to usual dosing to achieve therapeutic blood concentrations. Individuals with homozygous *3/*3 genotype are CYP3A5 nonexpressers. CYP3A5 nonexpression is the most frequent phenotype in most ethnic populations, except blacks. Differences between CYP3A5 genotypes in tacrolimus disposition have not translated into differences in clinical outcomes, such as acute rejection and graft survival. Therefore, although genotype-based dosing may improve achievement of therapeutic drug concentrations with empiric dosing, its role in clinical practice is unclear. CYP3A5 genotype may predict differences in absorption of extended-release and immediate-release oral formulations of tacrolimus. Two studies found that CYP3A5 expressers require higher doses of tacrolimus in the extended-release formulation compared to immediate release. CYP3A5 genotype plays a role in determining the impact of interacting drugs, such as fluconazole, on tacrolimus pharmacokinetics. Evidence conflicts regarding the impact of CYP3A5 genotype on risk of nephrotoxicity associated with tacrolimus. Further study is required.

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Section: Which Genotype Is Relevant: Recipient or Donor?mentioning

confidence: 83%

CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment

Chen¹,

Prasad²

2018

PGPM

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“…[96] Torio et al also found a trend toward higher blood pressure in CYP3A5*1 carriers treated with a CNI, 6 and 24 months after kidney transplantation. [97] At present, it appears that CYP3A5 genotype may relate to an individual's risk of developing hypertension but there is no convincing evidence that SNPs in ABCB1, WNK4, or SPAK do the same (see reference [98] for an extensive review on the genetic basis of hypertension).…”

Section: Other Tac-related Adverse Eventsmentioning

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

120

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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“…Among them, CYP3A5 genotype is associated with a remarkable impact on Tac PK, while the effects of other genetic polymorphisms are limited or even contradictory [ 125 - 127 ]. A number of algorithms containing clinical and/or PG factors have been constructed to predict the requirement of Tac dose; meanwhile, retrospective and prospective trials have been conducted to verify these algorithms [ 87 , 125 , 128 - 134 ].…”

Section: Clinical Applicationmentioning

confidence: 99%

Pharmacokinetics, Pharmacodynamics and Pharmacogenetics of Tacrolimus in Kidney Transplantation

Liu

Zhang

et al. 2018

CDM

129

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Background: Tacrolimus (Tac, or FK506), a calcineurin inhibitor (CNI), is the first-line immu-nosuppressant which consists of the footstone as immunosuppressive regimens in kidney transplantation. However, the drug toxicity and the significant differences of pharmacokinetics (PK) and pharmacodynam-ics (PD) among individuals are hidden troubles for clinical application. Recently, emerging evidences of Tac pharmacogenetics (PG) regarding drug absorption, metabolism, disposition, excretion and response are discovered for better understanding of this drug.Method: We reviewed the published articles regarding the Tac PG and its effects on PK and PD in kidney transplantation. In addition, we summarized information on polygenic algorithms.Results: The polymorphism of genes encoding metabolic enzymes and transporters related to Tac were largely investigated, but the results were inconsistent. In addition to CYP3A4, CYP3A5 and P-gp (also known as ABCB1), single nucleotide polymorphisms (SNPs) might also affect the PK and PD parameters of Tac.Conclusion: The correlation between Tac PK, PD and PG is very complex. Although many factors need to be verified, it is envisaged that thorough understanding of PG may assist clinicians to predict the optimal starting dosage, help adjust the maintenance regimen, as well as identify high risk patients for adverse ef-fects or drug inefficacy

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Effect of CYP3A51/3 Polymorphism on Blood Pressure in Renal Transplant Recipients

Cited by 6 publications

References 11 publications

CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment

CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment

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

Pharmacokinetics, Pharmacodynamics and Pharmacogenetics of Tacrolimus in Kidney Transplantation

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