title: Role of pharmacogenetic in ribavirin outcome prediction and pharmacokinetics in an Italian cohort of HCV-1 and 4 patients.
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.
authors: Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy.
authors: Sarah
authors: S
authors: Allegra
authors: Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy. Electronic address: jessica.cusato@yahoo.it.
authors: Jessica
authors: J
authors: Cusato
authors: Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy.
authors: Amedeo
authors: A
authors: De Nicolò
authors: Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy.
authors: Lucio
authors: L
authors: Boglione
authors: Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy.
authors: Alberto
authors: A
authors: Gatto
authors: Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy.
authors: Giuseppe
authors: G
authors: Cariti
authors: Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy.
authors: Giovanni
authors: G
authors: Di Perri
authors: Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy.
authors: Antonio
authors: A
authors: D'Avolio
mesh_terms: D000328:Adult; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D016174:Hepacivirus / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000821:virology; D006801:Humans; D007558:Italy; D015810:Linkage Disequilibrium / Q000235:genetics; D016015:Logistic Models; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D015999:Multivariate Analysis; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012254:Ribavirin / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D026901:Membrane Transport Proteins; C065171:cif nucleoside transporter; D012254:Ribavirin
keywords: AK1; HNF4α; SLC