Sirolimus and Tacrolimus Trough Concentrations and Dose Requirements after Kidney Transplantation in Relation to CYP3A5 and MDR1 Polymorphisms and Steroids

Mourad, Michel; Mourad, Georges; Wallemacq, Pierre; Garrigue, Valérie; Bellingen, Christophe Van; Kerckhove, Valérie Van; Meyer, Martine De; Malaise, Jacques; Eddour, Djamila Chaïb; Lison, Dominique; Squifflet, Jean; Haufroid, Vincent

doi:10.1097/01.tp.0000174131.47469.d2

Cited by 108 publications

(69 citation statements)

References 34 publications

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“…Two studies found an effect of the CYP3A5*1 allele on SRL exposure. However, it was specifically in patients without CNI cotreatment (5,6 ), but this was not confirmed in a third study (7 ). In the study we report here, in which the number of patients was relatively large compared to those in previous studies, the results are not in favor of this effect either, despite the fact that patients received no CNI cotreatment, which may have concealed the genetic effect.…”

Section: Discussioncontrasting

confidence: 51%

“…There is currently no evidence supporting an influence of polymorphisms of the gene ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1] 8 (the P-gp-encoding gene) (4 ) on SRL pharmacokinetics and clinical outcomes in kidney transplant patients. On the other hand, controversial results have been published concerning the impact on SRL exposure of polymorphisms of the gene CYP3A (cytochrome P450, family 3, subfamily A) (5)(6)(7). The CYP3A5*3 allele (rs776746 AϾG), which results in a truncated enzyme (8 ), has been associated with higher SRL blood concentrations in kidney transplant recipients.…”

confidence: 99%

“…Sirolimus (SRL) 7 is an inhibitor of the mammalian target of rapamycin used as a second-line immunosuppressive drug in solid organ transplantation. It is a substrate of intestinal and hepatic cytochrome P450 3A (CYP3A) (1 ) and of the P-glycoprotein (P-gp) (2,3 ), which both contribute to its first-pass elimination and consequently to its low and variable bioavailability.…”

confidence: 99%

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Effect of CYP3A422, POR28, and PPARA rs4253728 on Sirolimus In Vitro Metabolism and Trough Concentrations in Kidney Transplant Recipients

et al. 2013

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BACKGROUND Recent studies have identified new candidate polymorphisms in the genes related to CYP3A activity or calcineurin inhibitor dose requirements in kidney transplant recipients. These genes and polymorphisms are CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) (rs35599367-C>T; *22); POR [P450 (cytochrome) oxidoreductase] (rs1057868-C>T; *28); and PPARA (peroxisome proliferator-activated receptor alpha) (rs4253728-G>A). We investigated the impact of these polymorphisms on sirolimus (SRL) in vitro hepatic metabolism, SRL trough concentrations (C0), and SRL adverse events in kidney transplant recipients. METHODS The clinical study included 113 stable kidney transplant patients switched from a calcineurin inhibitor to SRL (SRL C0 measured at 1, 3, and 6 months thereafter). We investigated SRL metabolism in vitro using human liver microsomes derived from individual donors (n = 31). Microsomes and patients were genotyped by use of Taqman® allelic discrimination assays. The effects of polymorphisms and covariates were studied using multilinear regression imbedded in linear mixed-effect models or logistic regressions. RESULTS In vitro, the CYP3A4*22 allele resulted in approximately 20% lower metabolic rates of SRL (P = 0.0411). No significant association was found between CYP3A4, CYP3A5, or PPARA genotypes and SRL dose, C0, or C0/dose in kidney transplant patients. POR*28 was associated with a minor but significant decrease in SRL log-transformed C0 [CT/TT vs CC, β = −0.15 (0.05); P = 0.0197] but this did not have any impact on the dose administered, which limited the relevance of the finding. After adjustment for nongenetic covariates and correction for false discovery finding, none of the single-nucleotide polymorphisms tested showed significant association with SRL adverse events. CONCLUSIONS These recently described polymorphisms do not seem to substantially influence the pharmacokinetics of SRL or the occurrence of SRL adverse events in kidney transplant recipients.

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Section: Discussioncontrasting

confidence: 51%

confidence: 99%

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Effect of CYP3A422, POR28, and PPARA rs4253728 on Sirolimus In Vitro Metabolism and Trough Concentrations in Kidney Transplant Recipients

et al. 2013

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“…However, the data in literature is controversial. While there were studies showing reduced oral bioavailability of sirolimus in CYP3A5 expressors (Anglicheau et al, 2005;Le Meur et al, 2006), similar association was not found in other studies (Mourad et al, 2005;Renders et al, 2007). Moreover, none of the studies could show the influence of ABCB1 genotype on sirolimus exposure (Anglicheau et al, 2005;Mourad et al, 2005;Renders et al, 2007).…”

Section: Mammalian Target Of Rapamycin Inhibitorsmentioning

confidence: 73%

Pharmacogenetics and Renal Transplantation

Cheung¹

2011

Kidney Transplantation - New Perspectives

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“…Such results have been reported previously in the literature concerning this polymorphism. [5][6][7][8][9][10] A previous study by Patel and associates studied the effect of CYP3A5 polymorphism on tacrolimus drug dosing in North Indian renal allograft recipients. 11 To our knowledge, the present study is the first study to show the association between CYP3A5 genetic polymorphism and tacrolimus drug level in a South Indian population.…”

Section: Discussionmentioning

confidence: 99%

Untitled

2015

Exp Clin Transplant

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Objectives: Tacrolimus is the cornerstone for immunosuppression in renal transplant and is metabolized by the cytochrome P 450 3A (CYP3A) subfamily of enzymes in the liver and small intestine. A polymorphism in intron 3 of the CYP3A5 gene affects the expression of this enzyme and tacrolimus trough blood levels. The purpose of this study was to identify the proportion of CYP3A5 gene polymorphisms in South Indian renal transplant patients and determine the effect of CYP3A5 gene polymorphisms on tacrolimus trough blood levels in patients with and without CYP3A5 expression. Materials and Methods:We included 25 adult patients who underwent renal transplant at Government Medical College, Trivandrum. All patients received tacrolimus (dose, 0.1 mg/kg/body weight, in 2 divided doses). Tacrolimus trough blood levels were determined on postoperative day 6. The CYP3A5 genotype analysis was performed by polymerase chain reaction amplification of target and detection by restriction fragment length polymorphism analysis. Results: The CYP3A5*1/*1 genotype was detected in 5 recipients (20%), *1/*3 genotype in 5 recipients (20%), and *3/*3 genotypes in 15 recipients (60%) of the total 25 graft recipients.Mean tacrolimus level in the CYP3A5*1/*1 group was 5.154 ng/mL (range, 4.42 to 6.5 ng/mL), CYP3A5*1/*3 group was 5.348 ng/mL (range, 3.1 to 9.87 ng/mL), and CYP3A5*3/*3 group was 9.483 ng/mL (range, 4.5 to14.1 ng/mL). Acute rejection episodes were significantly more frequent for CYP3A5*1/*1 homozygous patients (40%) than patients with CYP3A5*1/*3 (20%) or CYP3A5*3/*3 (13%) genotypes. Conclusions: Most patients carried the mutant allele CYP3A5*3 (A6986G). Tacrolimus drug level correlated well with presence or absence of CYP3A5 polymorphisms. Acute rejection episodes were more frequent in expressors, and they may require higher doses of tacrolimus. Similarly, tacrolimus nephrotoxicity was more frequent in nonexpressors. Therefore, CYP3A5 polymorphism analysis before renal transplant may help determine the optimal dose of tacrolimus in this population and prevent acute rejection episodes or tacrolimus toxicity.

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Sirolimus and Tacrolimus Trough Concentrations and Dose Requirements after Kidney Transplantation in Relation to CYP3A5 and MDR1 Polymorphisms and Steroids

Abstract: Unlike tacrolimus, sirolimus adjusted trough concentrations and dose requirements seem not affected by CYP3A5 and MDR1 polymorphisms. Adjusted-prednisone dose has a significant impact on tacrolimus and sirolimus dose requirements.

Cited by 108 publications

References 34 publications

Effect of CYP3A422, POR28, and PPARA rs4253728 on Sirolimus In Vitro Metabolism and Trough Concentrations in Kidney Transplant Recipients

Effect of CYP3A422, POR28, and PPARA rs4253728 on Sirolimus In Vitro Metabolism and Trough Concentrations in Kidney Transplant Recipients

Pharmacogenetics and Renal Transplantation

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Sirolimus and Tacrolimus Trough Concentrations and Dose Requirements after Kidney Transplantation in Relation to CYP3A5 and MDR1 Polymorphisms and Steroids

Abstract: Unlike tacrolimus, sirolimus adjusted trough concentrations and dose requirements seem not affected by CYP3A5 and MDR1 polymorphisms. Adjusted-prednisone dose has a significant impact on tacrolimus and sirolimus dose requirements.

Cited by 108 publications

References 34 publications

Effect of CYP3A4*22, POR*28, and PPARA rs4253728 on Sirolimus In Vitro Metabolism and Trough Concentrations in Kidney Transplant Recipients

Effect of CYP3A4*22, POR*28, and PPARA rs4253728 on Sirolimus In Vitro Metabolism and Trough Concentrations in Kidney Transplant Recipients

Pharmacogenetics and Renal Transplantation

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Effect of CYP3A422, POR28, and PPARA rs4253728 on Sirolimus In Vitro Metabolism and Trough Concentrations in Kidney Transplant Recipients

Effect of CYP3A422, POR28, and PPARA rs4253728 on Sirolimus In Vitro Metabolism and Trough Concentrations in Kidney Transplant Recipients