The impact of IL-10 and CYP3A5 gene polymorphisms on dose-adjusted trough blood tacrolimus concentrations in early post-renal transplant recipients

Chen, Zhaolin; Cheng, Xi; Zhang, Liwen; Tang, Ling‐Zhi; Fang, Yan; Chen, Hongxiao; Zhang, Lei; Shen, Adong

doi:10.1007/s43440-021-00288-2

Cited by 4 publications

(3 citation statements)

References 53 publications

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“…In addition, the upstream regulatory gene POR of CYP3A [12] and the immune genes IL-6 and IL-10 have also been reported to be related to the pharmacokinetics of tacrolimus. Still, the relevant studies could be more extensive and their results need further verification [13,14]. Therefore, the 20 metabolic genes of tacrolimus were detected.…”

Section: Introductionmentioning

confidence: 99%

A Physiologically Based Pharmacokinetic Approach to Recommend an Individual Dose of Tacrolimus in Adult Heart Transplant Recipients

Pei,

Li,

Zhou

et al. 2023

Pharmaceutics

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Tacrolimus is the principal immunosuppressive drug which is administered after heart transplantation. Managing tacrolimus therapy is challenging due to a narrow therapeutic index and wide pharmacokinetic (PK) variability. We aimed to establish a physiologically based pharmacokinetic (PBPK) model of tacrolimus in adult heart transplant recipients to optimize dose regimens in clinical practice. A 15-compartment full-PBPK model (Simbiology® Simulator, version 5.8.2) was developed using clinical observations from 115 heart transplant recipients. This study detected 20 genotypes associated with tacrolimus metabolism. CYP3A5*3 (rs776746), CYP3A4*18B (rs2242480), and IL-10 G-1082A (rs1800896) were identified as significant genetic covariates in tacrolimus pharmacokinetics. The PBPK model was evaluated using goodness-of-fit (GOF) and external evaluation. The predicted peak blood concentration (Cmax) and area under the drug concentration–time curve (AUC) were all within a two-fold value of the observations (fold error of 0.68–1.22 for Cmax and 0.72–1.16 for AUC). The patients with the CYP3A5*3/*3 genotype had a 1.60-fold increase in predicted AUC compared to the patients with the CYP3A5*1 allele, and the ratio of the AUC with voriconazole to alone was 5.80 when using the PBPK model. Based on the simulation results, the tacrolimus dosing regimen after heart transplantation was optimized. This is the first PBPK model used to predict the PK of tacrolimus in adult heart transplant recipients, and it can serve as a starting point for research on immunosuppressive drug therapy in heart transplant patients.

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Section: Introductionmentioning

confidence: 99%

A Physiologically Based Pharmacokinetic Approach to Recommend an Individual Dose of Tacrolimus in Adult Heart Transplant Recipients

Pei,

Li,

Zhou

et al. 2023

Pharmaceutics

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“…Although CYP450 and transporter (e.g. ABCB1 ) gene polymorphisms are important for individual variations in drug metabolism and pharmacodynamics, they do not fully explain such individual differences 8,9 . In a previous study (in press), according to the therapeutic window concentration of tacrolimus in liver transplantation, we recruited 78 patients with significantly different initial tacrolimus blood concentrations (C 0 >10 or <5 μg/L) following liver transplantation at the First Affiliated Hospital of Zhengzhou University.…”

Section: Introductionmentioning

confidence: 99%

“…ABCB1) gene polymorphisms are important for individual variations in drug metabolism and pharmacodynamics, they do not fully explain such individual differences. 8,9 In a previous study (in press), according to the therapeutic window concentration of tacrolimus in liver transplantation, we recruited 78 patients with significantly different initial tacrolimus blood concentrations (C 0 >10 or <5 μg/L) following liver transplantation at the First Affiliated Hospital of Zhengzhou University. Then corresponding donor liver samples were collected for the genotyping of CYP3A5 and other genes including ABCB1, which have been reported in the literature to be possibly related to tacrolimus metabolism (Tables S1, S2).…”

Section: Introductionmentioning

confidence: 99%

Effects of ABCB1 DNA methylation in donors on tacrolimus blood concentrations in recipients following liver transplantation

Shi

Liang

Gao

et al. 2022

Brit J Clinical Pharma

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Aims To investigate the effects of ABCB1 DNA methylation in donors on individual differences in tacrolimus blood concentrations following liver transplantation. Methods Twenty‐three donor liver samples carrying the CYP3A5*3/*3 genotype were classified into 2 groups based on their initial tacrolimus blood concentrations (C0 >10 μg/L or <5 μg/L) following liver transplantation. ABCB1 mRNA levels in liver tissues and HepG2 cells were determined by quantitative reverse transcriptase polymerase chain reaction. DNA methylation status in liver tissues and HepG2 cells was determined using Illumina 850 methylation chip sequencing technology and pyrosequencing. 5‐Aza‐2dC was used to reverse methylation in HepG2 cells. Intracellular tacrolimus concentrations were determined by liquid mass spectrometry. Results Genome‐wide methylation sequencing and pyrosequencing analyses showed that the methylation levels of 3 ABCB1 CpG sites (cg12501229, cg00634941 and cg05496710) were significantly different between groups with different tacrolimus concentration/dose (C0/D) ratios. ABCB1 mRNA expression in donor livers was found to be positively correlated with tacrolimus C0/D ratio (R = .458, P < .05). After treatment with 5‐Aza‐2‐Dc, the methylation levels of the ABCB1 CpG sites in HepG2 cells significantly decreased, and this was confirmed by pyrosequencing; there was also a significant increase in ABCB1 transcription, which induced a decrease in intracellular tacrolimus concentrations. Conclusion ABCB1 CpG site methylation affects tacrolimus metabolism in humans by regulating ABCB1 expression. Therefore, ABCB1 DNA methylation in donor livers might be an important epigenetic factor that affects tacrolimus blood concentrations following liver transplantation.

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Impact of IL-6 and IL-10 genotypes on tacrolimus dose requirements in kidney transplant recipients: Monte Carlo analysis

Stefanović,

Danković,

Cvetković

et al. 2024

Pharmacogenomics

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The impact of IL-10 and CYP3A5 gene polymorphisms on dose-adjusted trough blood tacrolimus concentrations in early post-renal transplant recipients

Cited by 4 publications

References 53 publications

A Physiologically Based Pharmacokinetic Approach to Recommend an Individual Dose of Tacrolimus in Adult Heart Transplant Recipients

A Physiologically Based Pharmacokinetic Approach to Recommend an Individual Dose of Tacrolimus in Adult Heart Transplant Recipients

Effects of ABCB1 DNA methylation in donors on tacrolimus blood concentrations in recipients following liver transplantation

Impact of IL-6 and IL-10 genotypes on tacrolimus dose requirements in kidney transplant recipients: Monte Carlo analysis

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