Ribavirin is phosphorylated by adenosine kinase 1 (AK1) and cytosolic 5'-nucleotidase 2 and it is transported into cells by concentrative nucleoside transporters (CNT) 2/3, coded by SLC28A2/3 genes, and equilibrative nucleoside transporters (ENT) 1/2, coded by SLC29A1/2 genes. We evaluated the association of some polymorphisms of IL28B, SLC28A2/3, SLC29A1, ABCB1, NT5C2, AK1, HNF4α genes and ribavirin treatment outcome and pharmacokinetics after 4weeks of therapy, in a cohort of HCV-1/4 Italian patients. Allelic discrimination was performed by real-time PCR; plasma concentrations were determined at the end of dosing interval (Ctrough) using an HPLC-UV method. Non response was negatively predicted by cryoglobulinemia and IL28B_rs12980275 AA genotype and positively by Metavir score; Metavir score, insulin resistance and SLC28A2_rs1060896 CA/AA and HNF4α_rs1884613 CC genotypes were negative predictive factors of SVR, whereas HCV viral load at baseline and IL28B_rs12980275 AA and rs8099917 TT genotypes positively predicted this outcome; RVR was negatively predicted by insulin resistance and positively by cryoglobulinemia and IL28B_rs12980275 AA genotype; Metavir score and insulin resistance were able to negatively predict EVR, whereas cryoglobulinemia and IL28B_rs12980275 AA genotype positively predicted it; at last, virological relapse was negatively predicted by IL28B_rs8099917 TT and AK1_rs1109374 TT genotypes, insulin resistance was a positive predictor factor. Concerning ribavirin pharmacokinetics, SLC28A2_rs11854488 TT was related to lower Ctrough levels; conversely patients with TC profile of SLC28A3_rs10868138 and SLC29A1_rs760370 GG genotype had higher ribavirin levels. These results might contribute to the clarification of mechanisms causing the individuality in the response to ribavirin containing therapy.

Role of pharmacogenetic in ribavirin outcome prediction and pharmacokinetics in an Italian cohort of HCV-1 and 4 patients

BOGLIONE, Lucio;
2015-01-01

Abstract

Ribavirin is phosphorylated by adenosine kinase 1 (AK1) and cytosolic 5'-nucleotidase 2 and it is transported into cells by concentrative nucleoside transporters (CNT) 2/3, coded by SLC28A2/3 genes, and equilibrative nucleoside transporters (ENT) 1/2, coded by SLC29A1/2 genes. We evaluated the association of some polymorphisms of IL28B, SLC28A2/3, SLC29A1, ABCB1, NT5C2, AK1, HNF4α genes and ribavirin treatment outcome and pharmacokinetics after 4weeks of therapy, in a cohort of HCV-1/4 Italian patients. Allelic discrimination was performed by real-time PCR; plasma concentrations were determined at the end of dosing interval (Ctrough) using an HPLC-UV method. Non response was negatively predicted by cryoglobulinemia and IL28B_rs12980275 AA genotype and positively by Metavir score; Metavir score, insulin resistance and SLC28A2_rs1060896 CA/AA and HNF4α_rs1884613 CC genotypes were negative predictive factors of SVR, whereas HCV viral load at baseline and IL28B_rs12980275 AA and rs8099917 TT genotypes positively predicted this outcome; RVR was negatively predicted by insulin resistance and positively by cryoglobulinemia and IL28B_rs12980275 AA genotype; Metavir score and insulin resistance were able to negatively predict EVR, whereas cryoglobulinemia and IL28B_rs12980275 AA genotype positively predicted it; at last, virological relapse was negatively predicted by IL28B_rs8099917 TT and AK1_rs1109374 TT genotypes, insulin resistance was a positive predictor factor. Concerning ribavirin pharmacokinetics, SLC28A2_rs11854488 TT was related to lower Ctrough levels; conversely patients with TC profile of SLC28A3_rs10868138 and SLC29A1_rs760370 GG genotype had higher ribavirin levels. These results might contribute to the clarification of mechanisms causing the individuality in the response to ribavirin containing therapy.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11579/113958
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