Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib

Abstract

This manuscript has been published online, prior to printing.Once the issue is complete and page numbers have been assigned, the citation will change accordingly.Purpose: Chronic imatinib exposure has been shown to result in upregulation of the ABCB1 (P-glycoprotein) and ABCG2 (BCRP) transporters in vitro, for which imatinib is a substrate. This finding, along a trend towards increasing imatinib clearance over time in patients, has resulted in the suggestion that pharmacokinetic resistance may be contributing to eventual treatment failure. Here, we sought to determine the effects of long-term imatinib exposure on apparent oral clearance and transporter expression in vivo.Results: Plasma and liver concentrations of imatinib did not change significantly (p > 0.1) over the course of treatment, suggesting that steady-state had been reached. There was no increase in Abcb1 or Abcg2 expression in liver samples, whereas expression of these transporters in intestinal samples was highly variable, and no increase was apparent.Methods: Male BALB/c mice were treated daily-times 5 with oral imatinib at a dose of 50 mg/kg for 4 consecutive weeks. Imatinib concentrations were measured in plasma and liver tissue prior to treatment and following each week of dosing. Western blotting of liver and intestinal tissue lysates was performed to assess expression of Abcb1 and Abcg2.Conclusions: Imatinib does not appear to cause upregulation of ABC transporters in the hepatic and intestinal compartments in mice. These data do not support the possibility that autoinduction contributes to the development of resistance to imatinib.

Drug Transporters and Imatinib Treatment: Implications for Clinical Practice

“…Furthermore, protein expression of Abcb1 and Bcrp1 in mice did not differ after long-term treatment with orally administered imatinib (60). After daily administration for 4 consecutive weeks, no upregulation of Abcb1 and Bcrp1 in mouse liver and intestinal tissues was found.…”

A Long-term Prospective Population Pharmacokinetic Study on Imatinib Plasma Concentrations in GIST Patients

“…Hence, there may be a change in activity or expression of drug transporters involved in facilitated or active transport of imatinib. However, drug uptake and efflux transporters have shown a limited effect on imatinib absorption and excretion (17,18), and in vivo data showed no upregulation of drug efflux transporters after long-term treatment with imatinib (19). So, up until now, key mediators of imatinib transport during absorption and elimination have not been identified.…”

Photodynamic therapy of cancer — Challenges of multidrug resistance

“…However, chronic exposure to imatinib was shown to result in upregulation of P-pg and BCRP transporters in Caco-2 cells, but this phenomenon was not reproducible in the hepatic and intestinal compartments in mice. 58,59 These preclinical and clinical studies suggest that the co-administration of a MRP inhibitor and PS might be a feasible strategy for PDT. Preclinical studies show that co-administration of imatinib mesylate and PS could indeed inhibit PS e®lux although their combination in clinical setting still needs to be optimized and validated.…”