Effects of the CYP3A5*3 variant on cyclosporine exposure and acute rejection rate in renal transplant patients: a meta-analysis

Tang, Huilin; Ma, Lulin; Xie, Hong‐Guang; Zhang, Ting; Yong-fang, HU

doi:10.1097/fpc.0b013e32833ccd56

Cited by 32 publications

(22 citation statements)

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“…Thus, CsA pharmacokinetic time points and patient ethnicity affected the association between CYP3A5*3C and CsA pharmacokinetics. Furthermore, a metaanalysis suggested that CYP3A5*3 correlates with CsA pharmacokinetics in Asians [23] . An LD has been observed between CYP3A4*1G and CYPE3A5*3C carriers in Asian populations [24] .…”

Section: Discussionmentioning

confidence: 99%

Association of CYP3A polymorphisms with the pharmacokinetics of cyclosporine A in early post-renal transplant recipients in China

et al. 2012

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Aim: To evaluate retrospectively the association of cytochrome P450 3A (CYP3A) and ATP-binding cassette sub-family B member 1 (ABCB1) gene polymorphisms with the pharmacokinetics of cyclosporine A (CsA) in Chinese renal transplant patients. Methods: One hundred and twenty-six renal transplant patients were recruited. Blood samples were collected, and corresponding clinical indices were recorded on the seventh day after the procedure. The patients were genotyped for CYP3A4*1G, CYP3A5*3C, ABCB1 1236 C>T, ABCB1 2677 G>T/A, and ABCB1 3435 C>T polymorphisms. Whole blood trough concentrations of CsA at time zero (C 0 ) were measured before the drug administration. A multiple regression model was developed to analyze the effects of genetic factors on the CsA dose-adjusted C 0 (C 0 /dose) based on several clinical indices. Results: The CYP3A5*3C polymorphism influenced the C 0 and C 0 /dose of CsA, which were significantly higher in patients with the GG genotype than in patients with the AA or GA genotypes. No significant differences were detected for other SNPs (CYP3A4*1G, ABCB1 1236 C>T, ABCB1 2677 G>T/A, and ABCB1 3435 C>T). In a univariate analysis using Pearson's correlation test, age, hemoglobin, blood urea nitrogen and blood creatinine levels were significantly correlated with the log-transformed CsA C 0 /dose. In the multiple regression model, CYP3A5*3C, age, hemoglobin and blood creatinine level were associated with the log-transformed CsA C 0 /dose. Conclusion: CYP3A5*3C correlates with the C 0 /dose of CsA on the seventh day after renal transplantation. The allele is a putative indicator for the optimal CsA dosage in the early phase of renal transplantation in the Chinese population.

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Section: Discussionmentioning

confidence: 99%

Association of CYP3A polymorphisms with the pharmacokinetics of cyclosporine A in early post-renal transplant recipients in China

et al. 2012

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“…A meta-analysis of CYP3A5*3 in 1821 kidney transplant recipients concluded that CYP3A5*3 may have a small effect on cyclosporine pharmacokinetics but is not likely clinically relevant (44). Likewise, a recent review of ABCB1 determined a lack of consistent effect on cyclosporine pharmacokinetics, though it might be important in nephrotoxicity (discussed below) (27).…”

Section: Calcineurin Inhibitors and Pharmacokinetic Phenotypesmentioning

confidence: 99%

“…A summary of these are in Table 2. Acute rejection is commonly investigated, but studies to date have not shown a strong association of pharmacogenes with acute rejection in kidney transplant recipients treated with calcineurin inhibitors, as lately reviewed (13, 44). A recent meta-analysis confirmed that CYP3A5 and ABCB1 have minimal effect on acute rejection in tacrolimus treated patients (24).…”

Section: Calcineurin Inhibitors and Pharmacodynamic Phenotypesmentioning

confidence: 99%

Role of pharmacogenomics in dialysis and transplantation

Birdwell

2014

Current Opinion in Nephrology and Hypertension

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Purpose of Review Pharmacogenomics is the study of differences in drug response based on individual genetic background. With rapidly advancing genomic technologies and decreased costs of genotyping, the field of pharmacogenomics continues to develop. Application to patients with kidney disease provides growing opportunities for improving drug therapy. Recent Findings Pharmacogenomics studies are lacking in patients with chronic kidney disease and dialysis but are abundant in the kidney transplant field. A clinically actionable genetic variant exists in the CYP3A5 gene, with the initial tacrolimus dose selection optimized based on CYP3A5 genotype. Though many pharmacogenomics studies have focused on transplant immunosuppression pharmacokinetics, an expanding literature on pharmacodynamic outcomes like calcineurin inhibitor toxicity and new onset diabetes is providing new information on patients at risk. Summary Appropriately powered pharmacogenomics studies with well-defined phenotypes are needed to validate existing studies and unearth new findings in patients with kidney disease, especially the chronic kidney disease and dialysis population.

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“…The CYP3A5 * 3 allele is associated with reduced CYP3A5 enzyme activity (13). CYP3A5 * 3 has not been shown to be a clinically important in the metabolism of cyclosporine so it was not genotyped in the cyclosporine recipients (14)(15)(16). Pretransplant recipient DNA was isolated from lymphocytes obtained from peripheral blood after RBC lysis, with DNA purity and concentration determined by ultraviolet spectroscopy (Thermo Scientific, Wilmington, DE).…”

Section: Genotyping For Cyp3a5 * 3 In the Tacrolimus Recipientsmentioning

confidence: 99%

Lower Calcineurin Inhibitor Doses in Older Compared to Younger Kidney Transplant Recipients Yield Similar Troughs

Jacobson

Schladt

Oetting

et al. 2012

American Journal of Transplantation

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The number of older adults undergoing kidney transplantation has increased, yet little is known about calcineurin inhibitor (CNI) metabolism in this group. We studied CNI troughs and doses to determine if there were age related differences in metabolism and dose requirements. We studied 348 young (18–34 years), 1831 middle (35–64 years) and 374 older (65–84 years) adult kidney transplant recipients enrolled in a 7-center prospective study. Troughs were obtained from each patient 2x/week in weeks 1–8 and 2x/month in months 3–6. A multivariable linear mixed model examined the effect of age on log dose and weight normalized troughs. Older recipients had higher normalized tacrolimus troughs than middle or young age adults despite receiving doses a median of 1–2 mg/day lower. Age and CYP3A5*1 genotype had the largest effect on tacrolimus troughs. Older recipients also had higher normalized cyclosporine troughs than middle or young adults despite receiving median doses 100 mg/day lower. After normalization for dose and weight, CNI troughs were more than 50% higher in older adults than young adults. These data support age related changes in CNI metabolism. Further studies are needed to determine optimal dosing of CNIs in the elderly.

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Effects of the CYP3A5*3 variant on cyclosporine exposure and acute rejection rate in renal transplant patients: a meta-analysis

Abstract: We concluded that the CYP3A5*3 variant could be associated, to a certain extent, with increased CsA dose-adjusted C0 in blood and reduced mean daily doses, but that this genetic variant allele seemed to have little effect on the acute rejection rate in renal transplant patients taking CsA.

Cited by 32 publications

References 50 publications

Association of CYP3A polymorphisms with the pharmacokinetics of cyclosporine A in early post-renal transplant recipients in China

Association of CYP3A polymorphisms with the pharmacokinetics of cyclosporine A in early post-renal transplant recipients in China

Role of pharmacogenomics in dialysis and transplantation

Lower Calcineurin Inhibitor Doses in Older Compared to Younger Kidney Transplant Recipients Yield Similar Troughs

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