ABCB1 haplotypes do not influence transport or efficacy of tyrosine kinase inhibitors in vitro
نویسندگان
چکیده
Single-nucleotide polymorphisms (SNPs) in the gene coding for the efflux-transport protein ABCB1 (P-glycoprotein) are commonly inherited as haplotypes. ABCB1 SNPs and haplotypes have been suggested to influence the pharmacokinetics and therapeutic outcome of the tyrosine kinase inhibitor (TKI) imatinib, used for treatment of chronic myeloid leukemia (CML). However, no consensus has yet been reached with respect to the significance of variant ABCB1 in CML treatment. Functional studies of variant ABCB1 transport of imatinib as well as other TKIs might aid the interpretation of results from in vivo association studies, but are currently lacking. The aim of this study was to investigate the consequences of ABCB1 variant haplotypes for transport and efficacy of TKIs (imatinib, its major metabolite N-desmethyl imatinib [CGP74588], dasatinib, nilotinib, and bosutinib) in CML cells. Variant haplotypes - including the 61A>G, 1199G>A, 1236C>T, 1795G>A, 2677G>T/A, and 3435T>C SNPs - were constructed in ABCB1 complementary DNA and transduced to K562 cells using retroviral gene transfer. The ability of variant cells to express ABCB1 protein and protect against TKI cytotoxicity was investigated. It was found that dasatinib and the imatinib metabolite CGP74588 are effectively transported by ABCB1, while imatinib, nilotinib, and bosutinib are comparatively weaker ABCB1 substrates. None of the investigated haplotypes altered the protective effect of ABCB1 expression against TKI cytotoxicity. These findings imply that the ABCB1 haplotypes investigated here are not likely to influence TKI pharmacokinetics or therapeutic efficacy in vivo.
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عنوان ژورنال:
دوره 6 شماره
صفحات -
تاریخ انتشار 2013