Weight of ABCB1 and POR genes on oral tacrolimus exposure in CYP3A5 nonexpressor pediatric patients with stable kidney transplant

Almeida-Paulo, Gonzalo N.; García, I Dapía; Lubomirov, Rubin; Borobia, Alberto M.; Alonso-Sánchez, N L; Espinosa, Laura; Sansuán, Antonio J. Carcas

doi:10.1038/tpj.2016.93

Cited by 12 publications

(6 citation statements)

References 44 publications

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“…However, no differences were observed in AR by SNP genotype . Another study suggested that SNPs in the POR , ABCB1 and CYP3A5 genes should all be considered when dosing TAC . Optimal dosing of immune suppressants may lead to lower rates of AR.…”

Section: Pharmacogenomics and Acute Rejectionmentioning

confidence: 99%

Genetics of acute rejection after kidney transplantation

et al. 2017

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SUMMARY Treatment of acute rejection (AR) following kidney transplantation has improved in recent years, but there are still limitations to successful outcomes. This review article covers literature in regard to recipient and donor genetics of AR kidney and secondarily of liver allografts. Many candidate gene and some genome-wide association studies (GWASs) have been conducted for AR in kidney transplantation. Genetic associations with AR in kidney and liver are mostly weak, and in most cases, the associations have not been reproducible. A limitation in the study of AR is the lack of sufficiently large populations that account for population stratification to study the AR phenotype which in this era occurs in <10% of transplants. Furthermore, the AR phenotype has been difficult to define and the definitions of classifications have evolved over time. Literature related to the pharmacogenomics of tacrolimus is robust and has been validated in many studies. Associations between gene expression and AR are emerging as markers of outcomes and AR classification. In the future, combinations of pretransplant genotype for AR risk prediction, genotype-based immune suppressant dosing, and pharmacogenomic markers to select AR maintenance or treatment and expression markers from biopsies may provide valuable clinical tools for guiding treatment.

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Section: Pharmacogenomics and Acute Rejectionmentioning

confidence: 99%

Genetics of acute rejection after kidney transplantation

et al. 2017

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“… 13 In addition, tacrolimus is a substrate of the transporter p-glycoprotein (P-gp), which is also known as ATP-binding cassette subfamily B member 1 (ABCB1); however, the effect of ABCB1 in the pharmacokinetics of tacrolimus remains controversial. 14 , 15 Drug–drug interaction is another important factor that affects tacrolimus disposition. PopPK studies have identified the effect of prednisolone and calcium channel blockers on tacrolimus pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

Wuzhi Capsule Dosage Affects Tacrolimus Elimination in Adult Kidney Transplant Recipients, as Determined by a Population Pharmacokinetics Analysis

Chen¹,

Yang²,

Wang³

et al. 2021

PGPM

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Purpose In this study, we aimed to establish a tacrolimus population pharmacokinetic model and better understand the drug-drug interaction between Wuzhi capsule and tacrolimus in Chinese renal transplant recipients. Patients and Methods We performed a population pharmacokinetic analysis using a non-linear mixed-effects model to determine the suitable Wuzhi capsule dose in combination with tacrolimus. Data on 1378 tacrolimus steady-state concentrations were obtained from 142 patients who received kidney transplant in Changhai Hospital and Huashan Hospital. Demographic characteristics, laboratory tests, genetic polymorphisms, and co-medications were evaluated. Results The one-compartment model best described data. Our final model identified creatinine clearance rate, hematocrit, Wuzhi capsule dose, CYP3A5*3 genetic polymorphisms, and tacrolimus daily dose as significant covariates for tacrolimus clearance, with the value of 14.4 L h −1 , and the between-subject variability (BSV) was 25.4%. The Wuzhi capsule showed a dose-dependent effect on tacrolimus pharmacokinetics, demonstrating a stronger inhibitory effect than inductive effect. Conclusion Our model can accurately describe population pharmacokinetics of tacrolimus when combined with different doses of Wuzhi capsule. Additionally, this model can be used for individualizing tacrolimus dose following kidney transplantation.

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“…In vivo studies indicated that CYP3A4 activity was not affected by the POR*28 polymorphism [21,24,44]. However, there are reports showing that the activity was increased [22,49] and others suggesting that it was decreased [25]. Furthermore, a study that investigated the effect of the POR*28 polymorphism on the pharmacokinetics of cyclosporine, which is primarily metabolized by CYP3A4, suggested that the POR*28 polymorphism had little effect on CYP3A4 activity [23].…”

Section: Discussionmentioning

confidence: 99%

“…POR*28 leads to an amino acid substitution (A503V), which affects the flavin adenine dinucleotide-binding site of POR and is believed to alter its reactivity toward CYP enzymes [19,20]. Recently, several reports have demonstrated, mainly in renal transplant recipients, that the POR*28 polymorphism enhances TAC metabolism through excessive activation of CYP3A5 [21][22][23][24][25]. Some reports have shown that POR*28 (T-allele) carriers had significantly lower TAC C/D ratio than non-carriers in CYP3A5 expressors but not in CYP3A5 defective [21,24], whereas others have shown that the POR*28 polymorphism reduces the TAC C/D ratio regardless of the presence or absence of CYP3A5 expression [22,23].…”

Section: Introductionmentioning

confidence: 99%

Influence of POR28 Polymorphisms on CYP3A53-Associated Variations in Tacrolimus Blood Levels at an Early Stage after Liver Transplantation

Nakamura

Fukuda

Matsukane

et al. 2020

IJMS

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It is well known that the CYP3A5*3 polymorphism is an important marker that correlates with the tacrolimus dose requirement after organ transplantation. Recently, it has been revealed that the POR*28 polymorphism affects the pharmacokinetics of tacrolimus in renal transplant patients. In this study, we examined whether POR*28 as well as CYP3A5*3 polymorphism in Japanese recipients and donors would be another biomarker for the variation of tacrolimus blood levels in the recipients during the first month after living-donor liver transplantation. We enrolled 65 patients treated with tacrolimus, who underwent liver transplantation between July 2016 and January 2019. Genomic DNA was extracted from whole-blood samples, and genotyping was performed to examine the presence of CYP3A5*3 and POR*28 polymorphisms in the recipients and donors. The CYP3A5*3/*3 genotype (defective CYP3A5) of the recipient (standard partial regression coefficient [median C/D ratio of CYP3A5 expressor vs. CYP3A5 non-expressor, p value]: Pod 1–7, β= −0.389 [1.76 vs. 2.73, p < 0.001]; Pod 8–14, β = −0.345 [2.03 vs. 2.83, p < 0.001]; Pod 15–21, β= −0.417 [1.75 vs. 2.94, p < 0.001]; Pod 22–28, β = −0.627 [1.55 vs. 2.90, p < 0.001]) rather than donor (Pod 1–7, β = n/a [1.88 vs. 2.76]; Pod 8–14, β = n/a [1.99 vs. 2.93]; Pod 15–21, β = −0.175 [1.91 vs. 2.94, p = 0.004]; Pod 22–28, β = n/a [1.61 vs. 2.67]) significantly contributed to the increase in the concentration/dose (C/D) ratio of tacrolimus for at least one month after surgery. We found that the tacrolimus C/D ratio significantly decreased from the third week after transplantation when the recipient carried both CYP3A5*1 (functional CYP3A5) and POR*28 (n = 19 [29.2%], median C/D ratio [inter quartile range] = 1.58 [1.39–2.17]), compared with that in the recipients carrying CYP3A5*1 and POR*1/*1 (n = 8 [12.3%], median C/D ratio [inter quartile range] = 2.23 [2.05–3.06]) (p < 0.001). In conclusion, to our knowledge, this is the first report suggesting that the POR*28 polymorphism is another biomarker for the tacrolimus oral dosage after liver transplantation in patients carrying CYP3A5*1 rather than CYP3A5*3/*3.

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Weight of ABCB1 and POR genes on oral tacrolimus exposure in CYP3A5 nonexpressor pediatric patients with stable kidney transplant

Cited by 12 publications

References 44 publications

Genetics of acute rejection after kidney transplantation

Genetics of acute rejection after kidney transplantation

Wuzhi Capsule Dosage Affects Tacrolimus Elimination in Adult Kidney Transplant Recipients, as Determined by a Population Pharmacokinetics Analysis

Influence of POR28 Polymorphisms on CYP3A53-Associated Variations in Tacrolimus Blood Levels at an Early Stage after Liver Transplantation

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Weight of ABCB1 and POR genes on oral tacrolimus exposure in CYP3A5 nonexpressor pediatric patients with stable kidney transplant

Cited by 12 publications

References 44 publications

Genetics of acute rejection after kidney transplantation

Genetics of acute rejection after kidney transplantation

Wuzhi Capsule Dosage Affects Tacrolimus Elimination in Adult Kidney Transplant Recipients, as Determined by a Population Pharmacokinetics Analysis

Influence of POR*28 Polymorphisms on CYP3A5*3-Associated Variations in Tacrolimus Blood Levels at an Early Stage after Liver Transplantation

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Influence of POR28 Polymorphisms on CYP3A53-Associated Variations in Tacrolimus Blood Levels at an Early Stage after Liver Transplantation