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Citation
Tags
HERO ID
9102200
Reference Type
Journal Article
Title
Relationship of CYP3A5 genotype and ABCB1 diplotype to tacrolimus disposition in Brazilian kidney transplant patients
Author(s)
Cusinato, DAC; Lacchini, R; Romao, EA; Moyses-Neto, M; Coelho, EB; ,
Year
2014
Is Peer Reviewed?
Yes
Journal
British Journal of Clinical Pharmacology
ISSN:
0306-5251
EISSN:
1365-2125
Publisher
WILEY
Location
HOBOKEN
Page Numbers
364-372
Language
English
PMID
24528196
DOI
10.1111/bcp.12345
Web of Science Id
WOS:000340244800014
URL
https://onlinelibrary.wiley.com/doi/10.1111/bcp.12345
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Abstract
Tacrolimus (TAC) is one of the most successful immunosuppressive drugs in transplantation. Its pharmacokinetics (PK) and pharmacogenetics (PG) have been extensively studied, with many studies showing the influence of CYP3A5 on TAC metabolism and bioavailability. However, data concerning the functional significance of ABCB1 polymorphisms are uncertain due to inconsistent results. We evaluated the association between ABCB1 diplotypes, CYP3A5 polymorphisms and TAC disposition in a cohort of Brazilian transplant recipients.Individuals were genotyped for the CYP3A5*3 allele and ABCB1 polymorphisms (2677G>A/T, 1236C>T, 3435C/T) using a TaqMan® PCR technique. Diplotypes were analyzed for correlation with the TAC dose-normalized ratio (Coâ:âdose).We genotyped 108 Brazilian kidney recipients for CYP3A5 (11% CYP3A5*1/*1; 31% CYP3A5*1/*3 and 58% CYP3A5*3/*3) and ABCB1 haplotypes (42% CGC/CGC; 41% GCG/TTT and 17% TTT/TTT). Homozygous subjects for the CYP3A5*3 allele or carriers of the ABCB1â TTT/TTT diplotype showed a higher Coâ:âdose ratio compared with wild type subjects [median (interquartile range) 130.2 (97.5-175.4) vs. 71.3 (45.6-109.0), P < 0.0001 and 151.8 (112.1-205.6) vs. 109.6 (58.1-132.9), P = 0.01, respectively]. When stratified for the CYP3A5*3 group, ABCB1â TTT/TTT individuals showed a higher Coâ:âdose ratio compared with non-TTT/TTT individuals [167.8 (130.4-218.0) vs. 119.4 (100.2-166.3), Pâ=â0.04]. Multivariate linear regression analysis showed that the effects of CYP3A5 polymorphisms and ABCB1 diplotypes remained significant after correction for confounding factors.CYP3A5 is the major enzyme responsible for the marked interindividual variability in TAC PK, but it cannot be considered alone when predicting dose adjustment because ABCB1 diplotypes also affect TAC disposition, showing independent and additive effects on the TAC dose-normalized concentration.
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