Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, Italy.
Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, Bologna, Italy.
Pharmacogenomics J. 2014 Aug;14(4):328-35. doi: 10.1038/tpj.2014.7. Epub 2014 Mar 4.
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.
本研究旨在探讨人类有机阳离子转运蛋白 1（hOCT1）、ABCB1 和 ABCG2 的跨膜转运体多态性对 33 名男性和 27 名女性（中位年龄和范围分别为 56 岁和 27-79 岁）慢性髓性白血病患者伊马替尼药代动力学的可能影响。进行了群体药代动力学分析，以研究每个患者的伊马替尼分布情况和转运体多态性的作用。结果表明，α1-酸性糖蛋白和 hOCT1 的 c.480C>G 基因型对表观药物清除率（CL/F）有显著影响，分别导致 CL/F 的个体间变异性（IIV）降低 20%和 10%（从 50.1 增加到 19.6%）。有趣的是，25 名携带至少一个 c.480G 多态性等位基因的患者的 CL/F 值明显低于 35 名 c.480CC 个体（平均值±标准差，9.6±1.6 与 12.1±2.3 l·h-1，分别；P<0.001）。总之，hOCT1 的 c.480C>G SNP 可能显著影响伊马替尼的药代动力学，支持在更大的患者群体中进行进一步分析。
