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Consequences of Genetic Polymorphisms for Sirolimus Requirements After Renal Transplant in Patients on Primary Sirolimus Therapy
Author(s) -
Anglicheau Dany,
Le Corre Delphine,
Lechaton Sophie,
LaurentPuig Pierre,
Kreis Henri,
Beaune Philippe,
Legendre Christophe,
Thervet Eric
Publication year - 2005
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2005.00745.x
Subject(s) - cyp3a5 , sirolimus , single nucleotide polymorphism , medicine , cyp3a4 , genotyping , calcineurin , pharmacogenetics , allele , transplantation , pharmacology , genotype , gene , biology , genetics , cytochrome p450 , metabolism
Sirolimus (SRL) is a substrate for cytochromes P‐450 3A and P‐glycoprotein, the product of the MDR1 gene. We postulated that single nucleotide polymorphisms (SNPs) of these genes could be associated with inter‐individual variations in SRL requirements. We then evaluated in 149 renal transplant recipients the effect of polymorphisms CYP3A4*1/*1B , CYP3A5*1/*3 and MDR1 SNPs in exon 12, 21 and 26 on SRL concentration/dose (C/D) ratio 3 months after sirolimus introduction. SRL C/D ratio was significantly higher in patients treated with calcineurin inhibitors. The CYP3A4*1B and CYP3A5*1 alleles were present in 17% and 21% of patients, respectively. When treated with a SRL‐based therapy and low‐dose steroids, patients carrying the CYP3A4*1B or the CYP3A5*1 alleles required significantly more SRL to achieve adequate blood trough concentrations (p < 0.01 and p < 0.02, respectively). None of the MDR1 SNPs was associated with the SRL concentration/dose ratio. These findings suggest that the variations in SRL requirements are secondary to both genetic and non‐genetic factors including pharmacokinetic interactions. In patients with SRL‐based therapy, genotyping of the CYP3As genes may help to optimize the SRL management in transplant recipients.