Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients.
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 < or = 0.05) and the concentration/dose ratio (P < or = 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.
Anglicheau
Dany
D
Unité INSERM UMR S490, Molecular Toxicology, Centre universitaire des Saints-Pères, Université René Descartes, 45 rue des Saints-Peres, 75006 Paris, France. Dany.Anglicheau@biomedicale. univ-paris5.fr
Verstuyft
Céline
C
Laurent-Puig
Pierre
P
Becquemont
Laurent
L
Schlageter
Marie-Hélène
MH
Cassinat
Bruno
B
Beaune
Philippe
P
Legendre
Christophe
C
Thervet
Eric
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000328:Adult; D004305:Dose-Response Relationship, Drug; D005091:Exons; D005260:Female; D019450:Genes, MDR / Q000235:genetics* / Q000502:physiology*; D005838:Genotype; D006085:Graft Survival; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D017433:Protein Structure, Secondary; D016559:Tacrolimus / Q000627:therapeutic use*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D016559:Tacrolimus