title: The c.480C>G polymorphism of hOCT1 influences imatinib clearance in patients affected by chronic myeloid leukemia.
abstract: The aim of the study was to investigate any possible influence of polymorphisms of transmembrane transporters human organic cation transporter 1 (hOCT1), ABCB1, ABCG2 on imatinib pharmacokinetics in 33 men and 27 women (median age and range, 56 and 27-79 years, respectively) affected by chronic myeloid leukemia. A population pharmacokinetic analysis was performed to investigate imatinib disposition in every patient and the role of transporter polymorphisms. Results showed that the α1-acid glycoprotein and the c.480C>G genotype of hOCT1 had a significant effect on apparent drug clearance (CL/F) being responsible, respectively, for a 20% and 10% decrease in interindividual variability (IIV) of CL/F (from 50.1 up to 19.6%). Interestingly, 25 patients carrying at least one polymorphic c.480 G allele had a significant lower CL/F value with respect to the 35 c.480CC individuals (mean±s.d., 9.6±1.6 vs 12.1±2.3 l h(-1), respectively; P<0.001). In conclusion, the hOCT1 c.480C>G SNP may significantly influence imatinib pharmacokinetics, supporting further analyses in larger groups of patients.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Di Paolo
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Polillo
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Capecchi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Cervetti
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Baratè
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, Bologna, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Angelini
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Guerrini
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Fontanelli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Arici
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ciabatti
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Grassi
authors.affiliation: 1] Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy [2] Istituto Toscano Tumori, Via Alderotti 86/N, Florence, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Bocci
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, Bologna, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Hrelia
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Danesi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Petrini
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Galimberti
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001549:Benzamides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D010879:Piperazines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D001549:Benzamides; D027702:Organic Cation Transporter 1; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate