Chronic Imatinib Mesylate Exposure Leads to Reduced Intracellular Drug Accumulation by Induction of the ABCG2 (BCRP) and ABCB1 (MDR1) Drug Transport Pumps.
Posted by rob on June 26, 2005 under Uncategorized | 
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Burger H, van Tol H, Brok M, Wiemer EA, de Bruijn EA, Guetens G, de Boeck G, Sparreboom A, Verweij J, Nooter K
Cancer Biol Ther. 2005 Jul 9; 4(7):
Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia’s, and gastrointestinal stromal tumors. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco2 cells as an in vitro model for intestinal drug transport, we found that continuous exposure (up to 100 days) with imatinib (10 muM) specifically upregulates the expression of ABCG2 (maximal approximately 17-fold) and ABCB1 (maximal approximately 5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco2 cells resulted in a approximately 50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- and ABCB1-mediated efflux, as a result of upregulated expression of these drug pumps. Both ABCG2 and ABCB1 are normally expressed in the gastrointestinal tract and it might be anticipated that drug-induced upregulation of these intestinal pumps could reduce the oral bioavailability of imatinib, representing a novel mechanism of acquired pharmacokinetic drug resistance in cancer patients that are chronically treated with imatinib.
Bro. Richard said,
Hmmm, does this mean that 1) Imatinib Mesylate becomes less effective over time? 2)IM resistance will delvelop in most patients? 3)Long-term IM use will cause resistance to other medications?
I’m certain that the researchers will want further studies but it would be great to have an interpretation aimed at lay people.
Rob said,
That was the first article I have seen along those lines. It will be interesting to see if there are further studies with that type of theory.
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