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

Abstract

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, 1236CϾT in exon 12, 2677GϾT,A in exon 21, and 3435CϾT 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 Յ 0.05) and the concentration/dose ratio (P Յ 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.

Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

“…The contribution of MDR1 genetic polymorphisms has also been extensively studied for the calcineurin inhibitors cyclosporine and tacrolimus, which show large interindividual differences in oral bioavailability. Though two studies in renal transplant patients found cyclosporine and tacrolimus dose requirement to be higher in individuals homozygous for the 3435T allele (44,45), two other studies investigating tacrolimus steady-state dose requirement found an opposite effect, with plasma levels being lower in the 3435CC group after 3, 6, and 12 months (46,47). A recent study investigating the effect of genetic polymorphisms in CYP3A4, CYP3A5, and MDR1 on the pharmacokinetics of cyclosporine and tacrolimus also found no evidence supporting a role for the MDR1 C3435T polymorphism in dose requirement of the two drugs, consistent with previous reports regarding cyclosporin A trough levels and MDR1 genotype (48,49).…”

“…No difference in cyclosporine and tacrolimus dose requirement [49] Renal transplant patients T-129C, C1236T, G2677T/A (Ala893Ser/Thr), C3435T Tacrolimus Higher tacrolimus dose requirement in carriers of the 2677T/A alleles [44] Pediatric heart transplant patients G2677T/A (Ala893Ser/Thr), C3435T Tacrolimus Higher tacrolimus blood levels at 6 and 12 months [47] Japanese women T-129C -Increased placental P-glycoprotein expression levels [22] Caucasian volunteers C1236T + G2677T/A (Ala893Ser/Thr) + C3435T…”

Genetic Polymorphisms in CYP3A5 and MDR1 Genes and Their Correlations With Plasma Levels of Tacrolimus and Cyclosporine in Renal Transplant Recipients

“…3,4 As regards the MDR1 gene, we analyzed a 2677GϾT,A substitution in exon 21 and a 1236CϾT substitution in exon 12, both of which other studies have shown to significantly contribute to altered concentrations of immunosuppressants. 5 …”

La pharmacogénétique : le lien entre gènes et réponse aux médicaments

“…[5,6]. ABCA1, le transporteur responsable de l'efflux du cholestérol entérocytaire au pôle basolatéral, n'est pas impliqué dans l'absorption intestinale du cholestérol [7][8][9]. De même, l'absorption intestinale du cholestérol n'est pas altérée chez des souris dépourvues de SRBI (scavenger receptor class B, type I), alors qu'in vitro, l'action de ce récepteur sélectif pour les esters …”

“…En cancérologie, le dépistage de la maladie de Gilbert (déficit partiel en glucuroconjugaison) est effectué lorsque l'on envisage un traitement par l'irinotécan 1 pour éviter des toxicités hématologiques ou digestives très graves [7]. Le développement de la pharmacogé-nétique intéresse directement d'autres classes thérapeutiques, par exemple les anticoagulants, les immunosuppresseurs ou les anti-protéases [8][9][10].…”