Pharmacogenetics of calcineurin inhibitors in Brazilian renal transplant patients

Pharmacogenetics of calcineurin inhibitors in Brazilian renal transplant patients

Author Santoro, Ana Google Scholar
Felipe, Claudia Rosso Autor UNIFESP Google Scholar
Tedesco-Silva, Helio Autor UNIFESP Google Scholar
Medina-Pestana, Jose O. Autor UNIFESP Google Scholar
Struchiner, Claudio J. Google Scholar
Ojopi, Elida B. Google Scholar
Suarez-Kurtz, Guilherme Google Scholar
Institution Inst Nacl Canc
Universidade Federal de São Paulo (UNIFESP)
Fundacao Oswaldo Cruz
Universidade de São Paulo (USP)
Abstract Aim: Polymorphisms in the CYP3A5 and ABCB1 genes have been investigated as modulators of the pharmacokinetics and clinical effects of cyclosporine (CSA) and tacrolimus (TAC) in European, North American and Asian populations, with controversial results. the extensive variation in worldwide frequency distribution of CYP3A5 and ABCB1 polymorphisms is a caveat against the extrapolation of these data to the heterogeneous and admixed Brazilian population. We investigated the effect of CYP3A5 and ABCB1 polymorphisms on CSA and TAC dose-adjusted trough concentration (C(0)/dose) in Brazilian renal transplant recipients, during the first 3 months post-transplantation. Materials & methods: Patients receiving CSA (n = 150) or TAC (n = 151) were genotyped for CYP3A5(star)3 (rs776746, 6986A>G), (star)6(rs10264272, 14690G>A) and (star) 7 (rs41303343, 27131-27132insT) and for ABCB1 1236C>T (rs1128503), 2677G>T/A (rs2032582) and 3435C>T (rs1045642) polymorphisms. We explored the effects of CYP3A5 and ABCB1 polymorphisms, clinical and demographical characteristics on CSA and TAC C(0)/dose under a two-step data ana-lysis strategy by fitting a longitudinal mixed-effects model to the data; first to select the important covariates under a univariate setting and then to fit the final multivariate model. Results: C(0)/dose of TAC was associated with the number of CYP3A5-defective alleles, in a gene-dose manner, throughout the observation period, whereas C0/dose of CSA was associated with body surface area and prednisone dosing. No other significant associations were detected. Conclusion: Individual adjustment of the initial TAC dose according to the CYP3A5 haplotypes comprising the CYP3A5(star)3, (star)6 and (star)7 defective alleles might prove beneficial to Brazilian renal transplant recipients and should be further investigated in prospective trials. Original submitted 5 April 2011; Revision submitted 4 May 2011
Keywords ABCB1
Brazil
calcineurin inhibitors
cyclosporine
CYP3A5
renal transplant
tacrolimus
Language English
Sponsor Financiadora de Estudos e Projetos (Finep)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)
Grant number Financiadora de Estudos e Projetos (Finep): 01.08.01230.00
Date 2011-09-01
Published in Pharmacogenomics. London: Future Medicine Ltd, v. 12, n. 9, p. 1293-1303, 2011.
ISSN 1462-2416 (Sherpa/Romeo, impact factor)
Publisher Future Medicine Ltd
Extent 1293-1303
Origin http://dx.doi.org/10.2217/PGS.11.70
Access rights Closed access
Type Article
Web of Science ID WOS:000295728800016
URI http://repositorio.unifesp.br/handle/11600/34039

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