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Association of the Multidrug Resistance-1 Gene Single-Nucleotide Polymorphisms with the Tacrolimus Dose Requirements in Renal Transplant Recipients

Dany Anglicheau^*,, Céline Verstuyft, Pierre Laurent-Puig^*, Laurent Becquemont, Marie-Hélène Schlageter, Bruno Cassinat, Philippe Beaune^*, Christophe Legendre and Eric Thervet^*,

*Unité INSERM UMR S490, Molecular Toxicology, Centre universitaire des Saints-Pères, Université René Descartes, Paris, France; Service de Néphrologie et de Transplantation Rénale, Hôpital Saint Louis, Paris, France; Service de Pharmacologie, Faculté de Médecine Saint Antoine, Université Pierre et Marie Curie, Paris, France; and Service de Médecine Nucléaire, Hôpital Saint Louis, Paris, France.

Correspondence to Dany Anglicheau, Unité INSERM U-490, Centre Universitaire des Saints-Pères, 45, rue des Saints-Pères, 75006 Paris, France; Phone: 33-1-42-86-22-16; Fax: 33-1-42-86-20-72;

ABSTRACT. The immunosuppressive drug tacrolimus, whose pharmacokinetic characteristics display large interindividual variations, is a substrate for P-glycoprotein (P-gp), the product of the multidrug resistance-1 (MDR1) gene. Some of the single nucleotide polymorphisms (SNP) of MDR1 reported correlated with the in vivo activity of P-gp. Because P-gp is known to control tacrolimus intestinal absorption, it was postulated that these polymorphisms are associated with tacrolimus pharmacokinetic variations in renal transplant recipients. The objective of this study was to evaluate in a retrospective study of 81 renal transplant recipients the effect on tacrolimus dosages and concentration/dose ratio of four frequent MDR1 SNP possibly associated with P-gp function (T-129C in exon 1b, 1236C>T in exon 12, 2677G>T,A in exon 21, and 3435C>T in exon 26). As in the general population, the SNP in exons 12, 21, and 26 were frequent (16, 17.3, and 22.2% for the variant homozygous genotype, respectively) and exhibited incomplete linkage disequilibrium. One month after tacrolimus introduction, exon 21 SNP correlated significantly with the daily tacrolimus dose (P 0.05) and the concentration/dose ratio (P 0.02). Tacrolimus dose requirements were 40% higher in homozygous than wild-type patients for this SNP. The concentration/dose ratio was 36% lower in the wild-type patients, suggesting that, for a given dose, their tacrolimus blood concentration is lower. Haplotype analysis substantiated these results and suggested that exons 26 and 21 SNP may be associated with tacrolimus dose requirements. Genotype monitoring of the MDR1 gene reliably predicts the optimal dose of tacrolimus in renal transplant recipients and may predict the initial daily dose needed by individual patients to obtain adequate immunosuppression. E-mail: Dany.Anglicheau@biomedicale. univ-paris5.fr

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