Kidney Transplant Research Today is a free monthly online journal that collates and summarizes the latest research about Kidney Transplant, including details on risks, prognosis, procedure, surgery, organ donation. | ||||||||
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Consequences of genetic polymorphisms for sirolimus requirements after renal transplant in patients on primary sirolimus therapy.Anglicheau D, Le Corre D, Lechaton S, Laurent-Puig P, Kreis H, Beaune P, Legendre C, Thervet E Unité INSERM UMR S490, Molecular Toxicology, Centre Universitaire des Saints-Pères, Université René Descartes, Paris, France. dany.anglicheau@univ-paris5.fr 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. Published 14 February 2005 in Am J Transplant, 5(3): 595-603.
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