CYP3A5 and PPARA genetic variants are associated with low trough concentration to dose ratio of tacrolimus in kidney transplant recipients

CYP3A5 and PPARA genetic variants are associated with low trough concentration to dose ratio of tacrolimus in kidney transplant recipients

Purpose Genetic polymorphisms have been associated with variation in the metabolism of tacrolimus (TAC) in kidney transplant patients. This study is aimed at assessing the impact of allelic variants of CYP3A5 and PPARA genes on the pharmacokinetics (PK) of TAC in Brazilian kidney transplant recipien...

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Bibliographic Details
Published in:European journal of clinical pharmacology Vol. 77; no. 6; pp. 879 - 886
Main Authors: Everton, Janaína B. F., Patrício, Fernando J. B., Faria, Manuel S., Ferreira, Teresa C. A., Romao, Elen A., Silva, Gyl E. B., Magalhães, Marcelo
Format: Journal Article
Language:English
Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-06-2021
Springer Nature B.V
Subjects:
Biomedical and Life Sciences
Biomedicine
Gene polymorphism
Genetic diversity
Genotyping
Homozygotes
Kidney transplantation
Kidney transplants
Peripheral blood
Pharmacogenetics
Pharmacokinetics
Pharmacology/Toxicology
Population studies
Tacrolimus
Tacrolimus
Pharmacokinetics
ratio
Kidney transplantation
PPARA
CYP3A5
Co/D ratio
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Summary:Purpose Genetic polymorphisms have been associated with variation in the metabolism of tacrolimus (TAC) in kidney transplant patients. This study is aimed at assessing the impact of allelic variants of CYP3A5 and PPARA genes on the pharmacokinetics (PK) of TAC in Brazilian kidney transplant recipients in the first-year post-transplant. Methods A total of 127 patients were included for genetic evaluation. Genomic DNA was isolated from peripheral blood and real-time PCR was used to analyze the main polymorphisms described for the genes CYP3A5 (rs776746; C  >  G ) and PPARA (rs4823613; A  >  G and rs4253728; G  >  A ). Results CYP3A5 expressors showed a lower Co/ dose ratio than non-expressors, with the median values of this parameter <1.01 ng/mL/mg in the first group at all evaluated times. Additionally, PPARA variant homozygotes had a lower Co/D ratio than wild allele carriers in the 12-month post-transplant period, with a median value of 0.65 ng/mL/mg. In the CYP3A5 expressers, the presence of the variant homozygous genotype PPARA was associated with a lower value of Co/D compared with the other genotypic groups at month 12. Conclusion In the population under study, polymorphisms on CYP3A5 and PPARA were identified as determining and independent factors associated with the reduction of Co/D of TAC. Thus, the genotyping of these genetic variants may be a useful tool for the individualized prescription of TAC in kidney transplant patients.
ISSN:0031-6970
1432-1041
DOI:10.1007/s00228-020-03076-8