Clinical and genetic factors affecting tacrolimus trough levels and drug-related outcomes in Korean kidney transplant recipients

Kim, In‐Wha; Moon, Y J.; Ji, Eunhee; Kim, Kyung Im; Han, Nayoung; Kim, Seong-Ju; Shin, Wonjae; Ha, Jong‐Won; Yoon, Ju-Duk; Lee, Hye Suk; Oh, Jung Mi

doi:10.1007/s00228-011-1182-5

Cited by 38 publications

(37 citation statements)

References 39 publications

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“…Many results have been inconsistent. 1,3, 9,[32][33][34] The current study demonstrated that Hb and Hct were associated with log-transformed tacrolimus C/D ratios, and Alb was near statistical significance using a simple linear regression model. Hb, Hct and Alb have been reported to be associated with tacrolimus pharmacokinetics in previous studies.…”

Section: Discussionmentioning

confidence: 56%

“…21) CYP3A5 rs776746 polymorphisms have been proven to be associated with tacrolimus pharmacokinetics in transplant patients. 3,9,11,12) The dose-modifying effect caused by CYP3A5 rs776746 in Asian populations including Chinese was higher than that found in White populations. 4) The phenomenon may be due to the ethnic difference in the allele frequency of rs776746 allele G between Asian populations (63.4-77.0%) and White populations (80.0-93.8%).…”

Section: Discussionmentioning

confidence: 88%

“…1,3) Genetic markers such as single nucleotide polymorphisms (SNPs) have been shown to be involved in individual variability in tacrolimus pharmacokinetics. 9,10) Individualized tacrolimus treatment should also take genetic markers into consideration. Tacrolimus is mainly metabolized by the CYP3A5 enzyme.…”

Section: Introductionmentioning

confidence: 99%

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Association of Hemoglobin Levels, CYP3A5, and NR1I3 Gene Polymorphisms with Tacrolimus Pharmacokinetics in Liver Transplant Patients

Chen

Guo

Shi

et al. 2014

Drug Metabolism and Pharmacokinetics

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Tacrolimus is a widely used immunosuppressant after organ transplantation. The narrow therapeutic window and individual variability in tacrolimus pharmacokinetics make management of this agent a great challenge. This study was undertaken to determine the association of clinical markers, cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5) and nuclear receptor subfamily 1, group I, member 3 (NR1I3) gene polymorphisms with tacrolimus pharmacokinetics. A total of 96 liver transplant patients were enrolled in the study. Tacrolimus dose-adjusted trough concentration (C/D ratio) and clinical markers were recorded for one month after transplantation. CYP3A5 and NR1I3 gene polymorphisms for both donor and recipient were genotyped. In single variable analysis, hemoglobin (Hb), hematocrit (Hct), donor CYP3A5, NR1I3 gene polymorphisms and recipient CYP3A5 gene polymorphisms were associated with log-transformed tacrolimus C/D ratios. Hb, donor CYP3A5, NR1I3 gene polymorphisms and recipient CYP3A5 gene polymorphisms showed association with log-transformed tacrolimus C/D ratios in the final multiple linear regression model. Donor CYP3A5 polymorphisms were the most important variant, accounting for 14.3% of total variation involved in tacrolimus pharmacokinetics. This information could be useful in developing individualized tacrolimus treatment after liver transplantation.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 88%

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Association of Hemoglobin Levels, CYP3A5, and NR1I3 Gene Polymorphisms with Tacrolimus Pharmacokinetics in Liver Transplant Patients

Chen

Guo

Shi

et al. 2014

Drug Metabolism and Pharmacokinetics

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“…The type of intervention analyzed does not allow direct clinical application of the results, but in view of the clinical importance of the problem and the reasons explained above, the results of this meta-analysis constitute a strong argument in favor of the conduction of clinical trials in which donor and recipient genotypes for the CYP3A5 polymorphism are considered in determining the tacrolimus starting dose, as described by Thervet [34], in renal transplant recipients, as well as the dose in the stable phase of transplant, as reported by several cohort studies on renal transplantation despite the use of dosage adjustments guided by therapeutic drug monitoring [35][36][37][38].…”

Section: Expressers Nonexpressersmentioning

confidence: 80%

Meta-analysis and systematic review of the effect of the donor and recipient CYP3A5 6986A>G genotype on tacrolimus dose requirements in liver transplantation

Rojas

Herrero

Bosó

et al. 2013

Pharmacogenetics and Genomics

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The presence of the CYP3A5 6986A>G polymorphism in the donor affects tacrolimus pharmacokinetics in the recipient, although only the evidence available for the first month after transplantation was of adequate quality for demonstrating a significant difference. The evidence provided here shows no effect of the recipient genotype; however, the quality of the evidence was low, thereby precluding the drawing of firm conclusions.

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“…Earlier studies that attempted to determine the association between the recipient genotype and CNI nephrotoxicity yielded inconclusive results [7,12,13,24,[26][27][28]. In this study, multivariate analysis did not show a direct association between the recipient CY-P3A5 genotype and CNI nephrotoxicity (Table 4).…”

Section: Discussionmentioning

confidence: 35%

The Cytochrome P450 3A5 Non-Expressor Kidney Allograft as a Risk Factor for Calcineurin Inhibitor Nephrotoxicity

et al. 2018

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Background: Tacrolimus is mainly metabolized by cytochrome P450 3A5 (CYP3A5), which is expressed in the liver. However, CYP3A5 is also expressed in the kidney tissue and may contribute to local tacrolimus clearance in the kidney allograft. We aimed to evaluate the association between the allograft CYP3A5 genotype and transplant outcomes. Methods: We conducted a retrospective cohort study at the King Chulalongkorn Memorial Hospital, Thailand, comparing 2 groups of donor and recipient CYP3A5 genotypes, the expressor (*1/*1 and *1/*3) and the non-expressor (*3/*3). The primary outcomes were allograft complications including calcineurin inhibitor (CNI) nephrotoxicity and acute rejection episode. Results: Of the 50 enrolled patients, 21 donors were expressors and 29 donors were the non-expressors. Tacrolimus trough concentrations were similar between the 2 genotypes. The incidence of CNI nephrotoxicity was higher in recipients with non-expressor donor genotype compared with the expressor donor genotype (72.4 vs. 33.3%, p = 0.006). CNI nephrotoxicity incidence was not different when recipient’s genotypes were compared. Multivariate analysis from Cox-regression showed a hazard ratio of 3.18 (p = 0.026) for CNI nephrotoxicity in the non-expressor compared with the expressor donor. The recipient CYP3A5 genotypes did not significantly contribute to CNI nephrotoxicity. Kaplan-Meier analysis demonstrated the lowest CNI nephrotoxicity-free survival in recipients with the expressor genotype who received allograft from the non-expressor donors (p = 0.005). Conclusion: In conclusion, our results suggest that donor CYP3A5 non-expressor genotype (*3/*3) is a risk for CNI nephrotoxicity.

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Clinical and genetic factors affecting tacrolimus trough levels and drug-related outcomes in Korean kidney transplant recipients

Cited by 38 publications

References 39 publications

Association of Hemoglobin Levels, CYP3A5, and NR1I3 Gene Polymorphisms with Tacrolimus Pharmacokinetics in Liver Transplant Patients

Association of Hemoglobin Levels, CYP3A5, and NR1I3 Gene Polymorphisms with Tacrolimus Pharmacokinetics in Liver Transplant Patients

Meta-analysis and systematic review of the effect of the donor and recipient CYP3A5 6986A>G genotype on tacrolimus dose requirements in liver transplantation

The Cytochrome P450 3A5 Non-Expressor Kidney Allograft as a Risk Factor for Calcineurin Inhibitor Nephrotoxicity

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