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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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dc.contributor.authorHill, C.R.
dc.contributor.authorJamieson, D.
dc.contributor.authorThomas, H.D.
dc.contributor.authorBrown, C.D.A.
dc.contributor.authorBoddy, A.V.
dc.contributor.authorVeal, G.J.
dc.date.issued2013
dc.descriptionData source: Figures & tables, https://doi.org/10.1016/j.bcp.2012.10.004
dc.description.abstractActinomycin 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 GI(50) 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 (GI(50) 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 (AUC(0-6 h) 242 vs. 152 mu g/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.
dc.identifier.citationBiochemical Pharmacology, 2013; 85(1):29-37
dc.identifier.doi10.1016/j.bcp.2012.10.004
dc.identifier.issn0006-2952
dc.identifier.issn1873-2968
dc.identifier.urihttps://hdl.handle.net/11541.2/133129
dc.language.isoen
dc.publisherElsevier
dc.relation.fundingCancer Research UK
dc.rightsCopyright 2012 Elsevier. This article is Open Access under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported (CC BY-NC-ND 3.0) license (https://creativecommons.org/licenses/by-nc-nd/3.0/)
dc.source.urihttps://doi.org/10.1016/j.bcp.2012.10.004
dc.subjectactinomycin D
dc.subjectABC transporters
dc.subjectcancer
dc.titleCharacterisation of the roles of ABCB1, ABCC1, ABCC2 and ABCG2 in the transport and pharmacokinetics of actinomycin D in vitro and in vivo
dc.typeJournal article
pubs.publication-statusPublished
ror.mmsid9916218586501831

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