engleski

Drug transporter and metabolic enzyme gene variants and fluvastatin adverse drug reactions in renal transplant recipients

BACKGROUND. Statin use in transplant recipients had been hindered by concern about adverse drug reactions (ADRs). Polymorphisms in genes encoding metabolic enzymes and drug transporters could be valuable predictors of fluvastatin ADRs. Fluvastatin is substrate of CYP2C9 and drug transporters ABCB1, ABCG2 and to a lesser extent of OATP1B1 and MRP2. METHODS. 52 renal transplant recipients (RTRs) that experienced fluvastatin induced ADRs and 52 control patients, were enrolled in the study. Blood samples of all participants were genotyped for CYP2C9*2, *3 ; ABCG2 421C>A ; ABCB1 2677C>T/A, 3435C>T, 1236C>T ; SLCO1B1 388 A>G, 521T>C ; MRP2 -24C>T, 1249G>A by means of Real-Time PCR methods. RESULTS. We found that variants of ABCG2 421C>A (p=0.005), CYP2C9*3 (p=0.012) and ABCB1 1236C>T (p=0.05), were associated with fluvastatin ADRs. Genotypes ABCG2 421CA, CYP2C9 *1/*3 and ABCB1 1236CC were statistically significantly more prevalent in the group of patients with adverse effects than in controls. Our results showed that polymorphism of ABCG2 gene (OR=3.81 ; 95% CI=1.27-11.45) is of more importance than of CYP2C9 (OR=2.44 ; 95% CI=1.05-5.71) and ABCB1 1236C>T (OR=2.38 ; 95% CI=1.04-5.47) in a subgroup of RTRs, being different from results of pharmacokinetic studies on healthy volunteers. Carriers of CYP2C9 mutant alleles (*2, *3), who had inhibitor in their therapy, had more than six times greater odds of having adverse effects than those without inhibitor in their therapy (OR=6.59 ; 95% CI=1.24-35.08). CONCLUSIONS. ABCG2, CYP2C9 and ABCB1 gene variants could be valuable predictors of fluvastatin ADRs. In real clinical settings pharmacogenetic predisposition could be of even more importance than in healthy volunteers.

Fluvastatin ; CYP2C9 ; ABCB1 ; ABCG2

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