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The c.480C>G polymorphism of hOCT1 influences imatinib clearance in patients affected by chronic myeloid leukemia

The Pharmacogenomics Journal volume 14, pages 328–335 (2014)Cite this article

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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.

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Acknowledgements

We thank Drs Francesco Ceccherini and Laura Galeotti, Phymtech, Pisa, for their critical review of the pharmacometric modelling adopted in the present study. Funds from the Regione Toscana to GC and the Ministry of Education, University and Research of Italy (MIUR, Grant number 2009TNXL9P) to SA are acknowledged. Furthermore, GB received a grant from Istituto Toscano Tumori.

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Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy,

    A Di Paolo, M Polillo, M Capecchi, G Cervetti, C Baratè, F Guerrini, G Fontanelli, R Arici, E Ciabatti, S Grassi, G Bocci, R Danesi, M Petrini & S Galimberti

  2. Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, Bologna, Italy,

    S Angelini & P Hrelia

  3. Istituto Toscano Tumori, Via Alderotti 86/N, Florence, Italy,

    G Bocci

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  1. A Di Paolo
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Correspondence to A Di Paolo.

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Di Paolo, A., Polillo, M., Capecchi, M. et al. The c.480C>G polymorphism of hOCT1 influences imatinib clearance in patients affected by chronic myeloid leukemia. Pharmacogenomics J 14, 328–335 (2014). https://doi.org/10.1038/tpj.2014.7

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