Long-Term Effects of
            <i>ABCB1</i>
            and
            <i>SXR</i>
            SNPs on the Systemic Exposure to Cyclosporine in Pediatric Kidney Transplant Patients

Ferraresso, Mariano; Belingheri, Mirco; Turolo, Stefano; Ghio, Luciana; Tirelli, Amedea Silvia; Grillo, Paolo; Lepore, Marta; Edefonti, Alberto

doi:10.2217/pgs.13.148

Cited by 12 publications

(7 citation statements)

References 45 publications

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“…In addition, for the two papers by Sing , only the recently published paper was included to avoid overlapping of sample. Therefore, a total of 13 studies conducted between 2001 and 2013 with 1293 kidney transplant recipients were included in this meta‐analysis. The literature search process is presented in fig.…”

Section: Resultsmentioning

confidence: 99%

“… conducted a meta‐analysis in 2008 but failed to demonstrate a definitive correlation between the ABCB1 C3435T SNP and alterations of P‐gp function that can result in altered pharmacokinetics of CsA. However, during the past 6 years, many new studies on the relationship between the pharmacokinetics of CsA and C3435T SNP in kidney transplant recipients have been reported. Therefore, a new meta‐analysis is required to re‐summarize the influence of C3435T SNP on the pharmacokinetics of CsA in different ethnic groups and at different time‐points after kidney transplantation, to extend the research by Jiang.…”

mentioning

confidence: 99%

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The Effect of ABCB1 C3435T Polymorphism on Cyclosporine Dose Requirements in Kidney Transplant Recipients: A Meta‐Analysis

Lee

Wang

Yang³

et al. 2015

Basic Clin Pharma Tox

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Cyclosporine A (CsA) is a substrate of the multi-drug efflux pump P-glycoprotein (P-gp) encoded by ABCB1. Among the various single nucleotide polymorphisms (SNPs) of ABCB1, C3435T has been extensively investigated to determine the relationship with the pharmacokinetics of CsA. However, the results are controversial. This meta-analysis was designed to evaluate the influence of C3435T SNP on the dose-adjusted trough (C 0 /D) and peak (C max /D) concentrations of CsA. Based on a literature search of four authoritative databases, 13 studies since 2001 concerning 1293 kidney transplant recipients were included. The results indicated a significant difference of C 0 /D and C max /D between 3435CC and 3435TT genotype carriers (weighted mean difference (WMD) of C 0 /D: 4.18 (ng ml À1 )/(mg kg À1 ), 95% CIs: 1.00-7.37, p = 0.01; WMD of C max /D: 20.85 (ng ml À1)/ (mg kg À1 ), 95% CIs: 2.25-39.46, p = 0.03). Subgroup analysis by ethnicity demonstrated that C 0 /D was lower in Asian CC versus TT genotype carriers (WMD = 10.32 (ng ml À1)/(mg kg À1 ), 95% CIs: 4.78-15.85, p = 0.0003) but did not vary by genotype for Caucasian recipients. Moreover, significant variation of C 0 /D was found at 1 week and 1-3 months after transplantation between CC and TT genotype carriers. Therefore, this meta-analysis showed a correlation between ABCB1 C3435T polymorphism and the dose-adjusted concentration of CsA. Patients with 3435CC genotype will require a higher dose of CsA to achieve target therapeutic concentrations when compared with 3435TT carriers after kidney transplantation, especially in the Asian population and especially during the early and middle time periods after transplantation.Cyclosporine A (CsA), a calcineurin inhibitor, has been widely used for kidney transplant recipients to avoid allograft rejection [1]. However, CsA has a narrow therapeutic index and large interindividual pharmacokinetic variability [2,3]. To achieve the desired efficacy and limit side-effects, the individual trough or peak CsA concentration is routinely monitored [4]. Exploring the factors behind the large interindividual variability of CsA will help to develop a more reasonable individualized dosage regimen for kidney transplantation recipients. Genetic polymorphisms of drug metabolism enzymes and drug transporters have recently been considered as an important determinant of pharmacokinetic variation [5,6].CsA is a substrate of the multi-drug efflux pump P-glycoprotein (P-gp), which acts as an ATP-dependent transmembrane transporter and limits the bioavailability of drugs by decreasing their absorption from the intestinal lumen and enhancing their excretion [7]. P-gp is encoded by the multidrug resistance gene-1 (ABCB1). More than 50 single nucleotide polymorphisms (SNPs) in the corresponding gene sequence (ABCB1) of P-gp have been identified to date. In particular, exon 12 (C1236T), exon 21 (G2677T/A) and exon 26 (C3435T) were shown to play an important role in the expression and function of P-gp and have a functional impact on the pharma...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

The Effect of ABCB1 C3435T Polymorphism on Cyclosporine Dose Requirements in Kidney Transplant Recipients: A Meta‐Analysis

Lee

Wang

Yang³

et al. 2015

Basic Clin Pharma Tox

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“…22 However, in larger cohorts, including 87 teenagers and 104 pediatric patients who underwent renal transplant, CYP3A5 * 3 was not associated with variation in cyclosporine pharmacokinetics. 19,27 Cyclosporine is also a substrate for p-glycoprotein; the influence of ABCB1 variants on cyclosporine pharmacokinetics have been studied in pediatric renal 19,27,28 and adult cardiac transplant 22,29,30 patients. In all three pediatric studies, ABCB1 genotype influenced cyclosporine concentrations, though in the adult cardiac transplant studies the effect was inconsistent and dependent on the time point studied.…”

Section: Maintenance Immunosuppressive Agents In Pediatric Cardiac Trmentioning

confidence: 99%

“…Three studies in pediatric renal transplant patients have demonstrated that carriers of rs3842689, a 6 base-pair deletion in the NR1I2 promoter, require lower cyclosporine doses. 28,31,32 …”

Section: Maintenance Immunosuppressive Agents In Pediatric Cardiac Trmentioning

confidence: 99%

Pharmacogenomics

Driest

Webber

2015

Circulation

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“…In recent years, >700 variations in nucleotide sequences of P-gp-encoding multidrug resistance 1 (MDR1) gene have been identified17. Some of them are associated with alterations in protein functions, consequently changing the pharmacokinetics of substrate drugs.…”

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confidence: 99%

Effect of MDR1 gene polymorphisms on mortality in paraquat intoxicated patients

Kim

Kwon

et al. 2016

Sci Rep

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Paraquat is a fatal herbicide following acute exposure. Previous studies have suggested that multidrug resistance protein 1 (MDR1) might help remove paraquat from the lungs and the kidney. MDR1 single-nucleotide polymorphisms (SNPs) are involved in the pharmacokinetics of many drugs. The purpose of this study was to determine whether MDR1 SNPs were associated with the mortality in paraquat intoxicated patients. We recruited 109 patients admitted with acute paraquat poisoning. They were genotyped for C1236T, G2677T/A, and C3435T single-nucleotide polymorphisms (SNPs) of MDR1 gene. Their effects on mortality of paraquat intoxicated patients were evaluated. Overall mortality rate was 66.1%. Regarding the C1236T of the MDR1 gene polymorphism, 21 (19.3%) had the wild type MDR1 while 88 (80.7%) had homozygous mutation. Regarding the C3435T MDR1 gene polymorphism, 37(33.9%) patients had the wild type, 23 (21.1%) had heterozygous mutation, and 49 (45.0%) had homozygous mutation. Regarding the G2677T/A MDR1 gene polymorphism, 38 (34.9%) patients had the wild type, 57 (52.3%) had heterozygous mutation, and 14 (12.8%) had homozygous mutation. None of the individual mutations or combination of mutations (two or three) of MDR1 SNP genotypes altered the morality rate. The mortality rate was not significantly different among SNP groups of patients with <4.0 μg/mL paraquat. In conclusion, MDR1 SNPs have no effect on the mortality rate of paraquat intoxicated patients.

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Long-Term Effects of ABCB1 and SXR SNPs on the Systemic Exposure to Cyclosporine in Pediatric Kidney Transplant Patients

Abstract: The presence of specific ABCB1 and SXR SNPs could significantly affect cyclosporine exposure during a kidney transplant patient's development from childhood to adulthood in a time-dependent fashion.

Cited by 12 publications

References 45 publications

The Effect of ABCB1 C3435T Polymorphism on Cyclosporine Dose Requirements in Kidney Transplant Recipients: A Meta‐Analysis

The Effect of ABCB1 C3435T Polymorphism on Cyclosporine Dose Requirements in Kidney Transplant Recipients: A Meta‐Analysis

Pharmacogenomics

Effect of MDR1 gene polymorphisms on mortality in paraquat intoxicated patients

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