The impact of CYP3A5 and MDR1 polymorphisms on tacrolimus dosage requirements and trough concentrations in pediatric renal transplant recipients.

Sireen Shilbayeh, Rawan Zmeili, Reham Issa Almardini

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Abstract

Previous international studies demonstrated significant heterogeneity in the tacrolimus (TAC) dose required to attain target blood concentrations, attributed to both genetic and ethnic factors. While the majority of previous reports on adult recipients of renal, heart and liver transplants have shown a significant effect of CYP3A5FNx013 single nucleotide polymorphisms (SNPs) on TAC pharmacokinetics (PKs), the impact of multidrug resistance protein 1 (MDR1) and SNPs remains controversial. Yet, similar data of TAC in pediatric populations, in whom the intra- and inter-subject variations are likely to be even greater, is currently limited. We aimed to examine the influence of various CYP3A5 and MDR1 genotypes on TAC dose requirements and PKs in the Jordanian pediatric renal transplant population. Thirty-eight patients were genotyped for CYP3A5FNx011 and FNx013 and MDR1 C3435T. Dose-adjusted trough concentrations (C 0 /D) and daily doses (D) were compared among different CYP3A5 and MDR1 genotypes in the early and maintenance phases post-transplant. Surprisingly, there were no significant differences in D, C 0 or C 0 /D among the genotypes of CYP3A5 or MDR1 polymorphisms in either the early or the maintenance phase after transplantation, whereas after combining the C 0 /D levels of MDR1 C allele expressers, noticeably lower TAC levels were observed as compared with the TT genotype. However, the difference became not significant beyond 3 months. Based on a pharmacogenetic evaluation, the independent impact of CYP3A5 SNPs on TAC PKs was not evident, demonstrating the need for further large-scale studies.

Original languageEnglish
Pages (from-to)1125-1136
Number of pages12
JournalSaudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia
Volume24
Issue number6
Publication statusPublished - 1 Nov 2013

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Cytochrome P-450 CYP3A
P-Glycoprotein
Tacrolimus
Pediatrics
Kidney
Genotype
Single Nucleotide Polymorphism
Pharmacokinetics
Transplants
Maintenance
Dilatation and Curettage
Pharmacogenetics
Protein C
Population
Transplant Recipients
Transplantation
Alleles
Liver

Cite this

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title = "The impact of CYP3A5 and MDR1 polymorphisms on tacrolimus dosage requirements and trough concentrations in pediatric renal transplant recipients.",
abstract = "Previous international studies demonstrated significant heterogeneity in the tacrolimus (TAC) dose required to attain target blood concentrations, attributed to both genetic and ethnic factors. While the majority of previous reports on adult recipients of renal, heart and liver transplants have shown a significant effect of CYP3A5FNx013 single nucleotide polymorphisms (SNPs) on TAC pharmacokinetics (PKs), the impact of multidrug resistance protein 1 (MDR1) and SNPs remains controversial. Yet, similar data of TAC in pediatric populations, in whom the intra- and inter-subject variations are likely to be even greater, is currently limited. We aimed to examine the influence of various CYP3A5 and MDR1 genotypes on TAC dose requirements and PKs in the Jordanian pediatric renal transplant population. Thirty-eight patients were genotyped for CYP3A5FNx011 and FNx013 and MDR1 C3435T. Dose-adjusted trough concentrations (C 0 /D) and daily doses (D) were compared among different CYP3A5 and MDR1 genotypes in the early and maintenance phases post-transplant. Surprisingly, there were no significant differences in D, C 0 or C 0 /D among the genotypes of CYP3A5 or MDR1 polymorphisms in either the early or the maintenance phase after transplantation, whereas after combining the C 0 /D levels of MDR1 C allele expressers, noticeably lower TAC levels were observed as compared with the TT genotype. However, the difference became not significant beyond 3 months. Based on a pharmacogenetic evaluation, the independent impact of CYP3A5 SNPs on TAC PKs was not evident, demonstrating the need for further large-scale studies.",
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T1 - The impact of CYP3A5 and MDR1 polymorphisms on tacrolimus dosage requirements and trough concentrations in pediatric renal transplant recipients.

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AU - Zmeili, Rawan

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N2 - Previous international studies demonstrated significant heterogeneity in the tacrolimus (TAC) dose required to attain target blood concentrations, attributed to both genetic and ethnic factors. While the majority of previous reports on adult recipients of renal, heart and liver transplants have shown a significant effect of CYP3A5FNx013 single nucleotide polymorphisms (SNPs) on TAC pharmacokinetics (PKs), the impact of multidrug resistance protein 1 (MDR1) and SNPs remains controversial. Yet, similar data of TAC in pediatric populations, in whom the intra- and inter-subject variations are likely to be even greater, is currently limited. We aimed to examine the influence of various CYP3A5 and MDR1 genotypes on TAC dose requirements and PKs in the Jordanian pediatric renal transplant population. Thirty-eight patients were genotyped for CYP3A5FNx011 and FNx013 and MDR1 C3435T. Dose-adjusted trough concentrations (C 0 /D) and daily doses (D) were compared among different CYP3A5 and MDR1 genotypes in the early and maintenance phases post-transplant. Surprisingly, there were no significant differences in D, C 0 or C 0 /D among the genotypes of CYP3A5 or MDR1 polymorphisms in either the early or the maintenance phase after transplantation, whereas after combining the C 0 /D levels of MDR1 C allele expressers, noticeably lower TAC levels were observed as compared with the TT genotype. However, the difference became not significant beyond 3 months. Based on a pharmacogenetic evaluation, the independent impact of CYP3A5 SNPs on TAC PKs was not evident, demonstrating the need for further large-scale studies.

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