Breast Cancer Resistance Protein Substrate and Inhibition Evaluation: Why, When, and How?

Abstract

We wish to thank Poirier et al. (2014) for their recently published manuscript, "The need for human breast cancer resistance protein substrate and inhibition evaluation in drug discovery and development: why, when, and how?" which attempted to contemporize many of the key concepts of breast cancer resistance protein (BCRP; ABCG2)-mediated drug disposition and drug interactions. Indeed, further contextualization of the relevance of BCRP is needed to improve the clinical translation and prediction of both perpetrator and victim drug-drug interactions related to this transporter. However, we noticed that the authors have missed some critically important concepts when referring to drugs that have complex permeability/efflux and atypical metabolism, whose disposition has been mechanistically uncovered by reverse translation (working from bedside back to the bench). These omissions resulted in the description of sulfasalazine as a poor BCRP substrate in humans, even though it is currently one of the two best available clinical BCRP probes along with rosuvastatin (Urquhart et al., 2008;Yamasaki et al., 2008;Kusuhara et al., 2012).The authors selectively used one specific clinical study as "proof" that "sulfasalazine PK was not affected in individuals with impaired BCRP function, nor when coadministered with [a BCRP inhibitor]" (Poirier et al., 2014). The study in question by Adkison et al. (2010) used oral sulfasalazine enteric-coated tablets and, in fact, surprisingly showed no significant pharmacokinetic changes with oral coadministration of the BCRP inhibitor, pantoprazole, or a significant genedose effect of the BCRP 421 C.A functional polymorphism. These results stand in stark contrast to three independent clinical studies using oral immediate-release sulfasalazine tablets and/or suspension formulation, where significant 2-to 4-fold increases in sulfasalazine exposure were observed in carriers of the BCRP 421 C.A polymorphism and during coadministration of an oral BCRP inhibitor (Urquhart et al., 2008;Yamasaki et al., 2008;Kusuhara et al., 2012), as well as three independent preclinical studies in Bcrp-knockout mice and rats (Zaher et al., 2006;Shukla et al., 2009;Zamek-Gliszczynski et al., 2012). As discussed by Adkison et al. (2010), an accidental flaw in the execution of their study demonstrated the importance of proper formulation selection (suspension or immediate release, but not extended release), rather than disproving the utility of sulfasalazine as a marker of BCRP activity in humans.Please allow us to elaborate on some subtle and important, although perhaps not apparently obvious, study caveats from the Adkison et al. (2010) study was confounded because the clinical site used an enteric-coated delayed-release formulation, which allowed sulfasalazine to bypass the majority of small-intestinal BCRP (ABCG2). Mechanistically, if a delayed-release tablet is administered, then sulfasalazine will not be available until the distal small intestine (ileum)/proximal large intestine (cecum), where BCRP expression ...

Response to “Breast Cancer Resistance Protein Substrate and Inhibition Evaluation: Why, When, and How?”

“…This was likewise not the intention of our article, in which we discussed BCRP-mediated transport assessment in drug development through new in vitro results as well as relevant published clinical studies. In agreement with Ware et al (2014), we recommend integrated, case-by-case approaches for BCRP evaluation, using all preclinical and clinical tools available.…”

“…This was not our intention, nor did we make such concrete statements in our article. Furthermore, we had cited all of the relevant references concerned with sulfasalazine, including the references cited by Ware et al (2014). In our Table 1 (Poirier et al, 2014), we indicated that the range for the sulfasalazine area under the curve changes from ,2-to 4-fold for pharmacogenetic studies and up to 3.2-fold for DDI studies.…”

“…We discussed the diverging (animal to human) and partly controversial data of sulfasalazine interactions with cautiousness and without making firm recommendations, stating that "It might therefore be a possibility that the mechanism of the sulfasalazine/curcumin interaction is not only an inhibition of BCRP but also an inhibition of the bacterial degradation of sulfasalazine in the intestine." This sentence was only partly cited by Ware et al (2014); by omitting the first part of the sentence, a wrong impression might be given.…”

“…We acknowledge the specific points raised by Ware et al (2014) concerning BCRP-sulfasalazine interaction studies and regret if our article might furnish the impression that sulfasalazine may not be a suitable substrate for in vivo DDI studies for BCRP inhibition. This was not our intention, nor did we make such concrete statements in our article.…”

“…We thank you for the opportunity to respond to the comments made by Ware et al (2014) on our recently published article "The Need for Human Breast Cancer Resistance Protein Substrate and Inhibition Evaluation in Drug Discovery and Development: Why, When, and How?" (Poirier et al, 2014).…”