Characterisation of the roles of ABCB1, ABCC1, ABCC2 and ABCG2 in the transport and pharmacokinetics of actinomycin D in vitro and in vivo

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  2. Christopher Hill
  3. Dr David Jamieson
  4. Huw Thomas
  5. Dr Colin Brown
  6. Professor Alan Boddy
  7. Dr Gareth Veal
Author(s)Hill CR, Jamieson D, Thomas HD, Brown CDA, Boddy AV, Veal GJ
Publication type Article
JournalBiochemical Pharmacology
Year2013
Volume85
Issue1
Pages29-37
ISSN (print)0006-2952
ISSN (electronic)1873-2968
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Actinomycin D plays a key role in the successful treatment of Wilms tumour. However, associated liver toxicities remain a drawback to potentially curative treatment. We have used MDCKII cells over-expressing ABCB1, ABCC1, ABCC2 and ABCG2, alongside knockout mouse models to characterise actinomycin D transport and its impact on pharmacokinetics. Growth inhibition, intracellular accumulation and cellular efflux assays were utilised. A 59-fold difference in GI50 was observed between MDCKII-WT and MDCKII-ABCB1 cells (12.7 nM vs. 745 nM, p < 0.0001). Reduced sensitivity was also seen in MDCKII-ABCC1 and ABCC2 cells (GI50 25.7 and 40.4 nM respectively, p < 0.0001). Lower intracellular accumulation of actinomycin D was observed in MDCKII-ABCB1 cells as compared to MDCKII-WT (0.98 nM vs. 0.1 nM, p < 0.0001), which was reversed upon ABCB1 inhibition. Lower accumulation was also seen in MDCKII-ABCC1 and ABCC2 cells. Actinomycin D efflux over 2 h was most pronounced in MDCKII-ABCB1 cells, with 5.5-fold lower intracellular levels compared to WT. In vivo studies showed that actinomycin D plasma concentrations were significantly higher in Abcb1a/1b−/− as compared to WT mice following administration of 0.5 mg/kg actinomycin D (AUC0–6 h 242 vs. 152 μg/L h respectively). While comparable actinomycin D concentrations were observed in the kidneys and livers of Abcb1a/1b−/− and Abcc2−/− mice, concentrations in the brain were significantly higher at 6 h following drug administration in Abcb1a/1b−/− mice compared to WT. Results confirm actinomycin D as a substrate for ABCB1, ABCC1 and ABCC2, and indicate that Abcb1a/1b and Abcc2 can influence the in vivo disposition of actinomycin D. These data have implications for ongoing clinical pharmacology trials involving children treated with actinomycin D.
PublisherElsevier Inc.
URLhttp://dx.doi.org/10.1016/j.bcp.2012.10.004
DOI10.1016/j.bcp.2012.10.004
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