title: Influence of single-nucleotide polymorphisms on deferasirox C trough levels and effectiveness.
abstract: Deferasirox (DFX) is the only once-daily oral chelator for iron overload and its pharmacokinetic has been related with response to therapy. Our aim was to evaluate DFX plasma concentrations according to single-nucleotide polymorphisms in genes involved in its metabolism (UGT1A1, UGT1A3, CYP1A1, CYP1A2 and CYP2D6) and elimination (MRP2 and BCRP1). Further aim was to define a plasma concentration cutoff value predicting an adequate response to therapy. Plasma concentrations were determined at the end of dosing interval (C trough) using an high-performance liquid chromatography-ultraviolet method. Allelic discrimination was performed by real-time PCR. C trough levels were influenced by UGT1A1C>T rs887829, CYP1A1C>A rs2606345, CYP1A2A>C rs762551, CYP1A2C>T rs2470890 and MRP2G>A rs2273697 polymorphisms. A DFX plasma efficacy cutoff value of 20,000 ng ml(-1) was identified; CYP1A1C>A rs2606345 AA and CYP1A2C>T rs2470890 TT genotypes may predict this value, suggesting a negative predictive role in therapy efficacy. Our data suggest the feasibility of a pharmacogenetic-based DFX dose personalization.
authors.affiliation: Laboratory of Clinical, Pharmacology and Pharmacogenetics, Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Cusato
authors.affiliation: Laboratory of Clinical, Pharmacology and Pharmacogenetics, Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Allegra
authors.affiliation: Centre for Microcitemie, Department of Paediatrics, S. Luigi Gonzaga Hospital, University of Turin, Turin, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Massano
authors.affiliation: Department of Biological and Clinical Sciences, S. Luigi Gonzaga Hospital, University of Turin, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: De Francia
authors.affiliation: Centre for Microcitemie, Department of Paediatrics, S. Luigi Gonzaga Hospital, University of Turin, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Piga
authors.affiliation: Laboratory of Clinical, Pharmacology and Pharmacogenetics, Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: D'Avolio
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000483:Alleles; D001565:Benzoates / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D015331:Cohort Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000077588:Deferasirox; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D019190:Iron Overload / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001565:Benzoates; D003577:Cytochrome P-450 Enzyme System; D000077588:Deferasirox; D014453:Glucuronosyltransferase; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D014230:Triazoles; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human