Why Clinical Modulation of Efflux Transport at the Human Blood–Brain Barrier Is Unlikely: The ITC Evidence-Based Position

Kalvass, J. Cory; Polli, Joseph W.; Bourdet, D.L.; Feng, Bo; Huang, Suli; Liu, X; Smith, QR; Zhang, LK; Zamek‐Gliszczynski, M J

doi:10.1038/clpt.2013.34

Cited by 181 publications

(232 citation statements)

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“…As such, we urge the authors to reconsider the conclusion that "A significant amount of discordance is apparent when comparing the observations in Bcrp knockout mice with that of clinical findings, the most significant of which is for sulfasalazine" (Poirier et al, 2014). This claimed "discordance" is an artifact of directly comparing partial intestinal BCRP inhibition to complete genetic ablation of both intestinal and systemic BCRP, a subject recently addressed by the International Transporter Consortium (Kalvass et al, 2013;Zamek-Gliszczynski et al, 2013). If the goal is to clarify when, why, and how BCRP is important in drug discovery and development, we recommend that an integrated approach to transporter biology remain a priority, where the totality of data (in vitro, preclinical, and clinical experiences) is used to predict and understand BCRP-mediated drug disposition and drug-drug interactions.…”

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confidence: 86%

“…This difference in Bcrp function between complete genetic ablation in Abcg22/2 animals and partial Bcrp inhibition by gefitinib was also acknowledged in the original publication by Zaher Shukla et al (2009). Indeed, this difference would be expected based on pharmacokinetic principles given that ABCG2 421 C.A polymorphism or coadministration of oral BCRP inhibitors represents partial inhibition of efflux function, and not complete ablation as in the gene-knockout models (ZamekGliszczynski et al, 2013). Furthermore, the contribution of intestinal versus systemic BCRP must be considered when comparing geneticknockout animals to oral inhibitors in the clinic because, as pointed out by the authors, intestinal BCRP is more prone to inhibition (i.e., exposed to far greater inhibitor concentrations) than systemic BCRP in humans (Kalvass et al, 2013;Zamek-Gliszczynski et al, 2013).…”

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confidence: 99%

“…Indeed, this difference would be expected based on pharmacokinetic principles given that ABCG2 421 C.A polymorphism or coadministration of oral BCRP inhibitors represents partial inhibition of efflux function, and not complete ablation as in the gene-knockout models (ZamekGliszczynski et al, 2013). Furthermore, the contribution of intestinal versus systemic BCRP must be considered when comparing geneticknockout animals to oral inhibitors in the clinic because, as pointed out by the authors, intestinal BCRP is more prone to inhibition (i.e., exposed to far greater inhibitor concentrations) than systemic BCRP in humans (Kalvass et al, 2013;Zamek-Gliszczynski et al, 2013). In this regard, it merits pointing out that in Bcrp-knockout mice, sulfasalazine exposure was increased an order of magnitude following intravenous administration (systemic BCRP contribution) and up to two orders of magnitude following oral administration (intestinal + systemic BCRP contribution) (Zaher et al, 2006).…”

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confidence: 99%

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

et al. 2014

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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 ...

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confidence: 86%

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confidence: 99%

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confidence: 99%

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

et al. 2014

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“…9 At an acceptable dose, 17%-58% of Pgp inhibition with tariquidar (2-8 mg/kg) and 38%-50% of Pgp inhibition with CS (2.5 mg/kg/h) were observed by evaluating Pgp inhibition on (R)-[ 11 C]-verapamil PET imaging. 18 However, interindividual variability regarding affinity and response to the substrate or inhibitor may also complicate the outcome when using a moderate dose of a Pgp inhibitor. 19 Our data also showed individual variability among all the participants, similar to that observed in previous studies.…”

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confidence: 99%

Clinical Applications of Simultaneous PET/MR Imaging Using (R)-[¹¹C]-Verapamil with Cyclosporin A: Preliminary Results on a Surrogate Marker of Drug-Resistant Epilepsy

Shin¹,

Chu

Shin

et al. 2015

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE:The development of resistance to antiepileptic drugs is explained well by the transporter hypothesis, which suggests that drug resistance is caused by inadequate penetration of drugs into the brain barrier as a result of increased levels of efflux transporter such as p-glycoprotein. To evaluate the brain expression of p-glycoprotein in patients with drug-resistant epilepsy, including neocortical epilepsy, we developed a noninvsive quantitative analysis including asymmetry indices based on (R)-[11 C]-verapamil

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“…OATP inhibition can be competitive (Zamek-Gliszczynski et al, 2013), which prompts the question of whether clarithromycin also is an OATP substrate? At a kinetic level, clarithromycin preferentially partitions into suspended rat hepatocytes, with an unbound liver-to-buffer partition coefficient of 6 (Yabe et al, 2011), an observation that could be explained by hepatic uptake (Smith et al, 2010;Kalvass et al, 2013). No mechanistic evidence exists for hepatic uptake of itraconazole or its major metabolite, hydroxyitraconazole, which also is an inhibitor of CYP3A (Templeton et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Clinical CYP3A Inhibitor Alternatives to Ketoconazole, Clarithromycin and Itraconazole, Are Not Transported into the Liver by Hepatic Organic Anion Transporting Polypeptides and Organic Cation Transporter 1

Higgins

Zamek‐Gliszczynski

2014

Drug Metab Dispos

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Ketoconazole is no longer available for clinical determination of worst-case victim drug-drug interaction (DDI) potential for cytochrome P450 3A (CYP3A)-substrate drugs; clarithromycin and itraconazole are the proposed replacements. Ketoconazole DDIs are described by unbound systemic exposures due to absence of carrier-facilitated hepatic uptake, but this aspect of clarithromycin and itraconazole disposition has not been investigated. At present, transport of clarithromycin, itraconazole, and hydroxyitraconazole by hepatic organic anion transporting polypeptides (OATPs) and organic cation transporter 1 (OCT1) was examined in vitro and in vivo. As for ketoconazole, uptake of clarithromycin, itraconazole, and hydroxyitraconazole into OATP1B1, OATP1B3, OATP2B1, and OCT1 expressing human embryonic kidney 293 (HEK293) cells was not greater than in vector controls. Uptake into these HEK293 cells and human hepatocytes was not impaired by the prototypical OATP, OCT, and sodium/taurocholate cotransporting polypeptide inhibitors bromosulfophthalein, imipramine, and taurocholate, respectively. In contrast, uptake of the positive controls, atorvastatin for OATPs and metformin for OCT1, was significantly enhanced by relevant transporter expression, and uptake into both these HEK293 cells and human hepatocytes was significantly impaired by prototypical inhibitors. In Oatp1a/1b gene cluster knockout mice, which lack the major hepatic Oatps, and in Oct1/2 knockout mice, ketoconazole, clarithromycin, itraconazole, and hydroxyitraconazole oral exposure was not increased, and the liver-to-blood partition coefficient (K p ) was not decreased. By contrast relative to wild-type mice, in Oatp1a/1b-and Oct1/2-knockout mice, atorvastatin and metformin oral exposure was significantly increased, and liver K p was significantly decreased. The present studies provide in vitro and in vivo evidence that, like ketoconazole, clarithromycin, itraconazole, and hydroxyitraconazole are not transported into the liver by hepatic uptake transporters, including OATPs and OCT1.

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Why Clinical Modulation of Efflux Transport at the Human Blood–Brain Barrier Is Unlikely: The ITC Evidence-Based Position

Cited by 181 publications

References 68 publications

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

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

Clinical Applications of Simultaneous PET/MR Imaging Using (R)-[¹¹C]-Verapamil with Cyclosporin A: Preliminary Results on a Surrogate Marker of Drug-Resistant Epilepsy

Clinical CYP3A Inhibitor Alternatives to Ketoconazole, Clarithromycin and Itraconazole, Are Not Transported into the Liver by Hepatic Organic Anion Transporting Polypeptides and Organic Cation Transporter 1

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Why Clinical Modulation of Efflux Transport at the Human Blood–Brain Barrier Is Unlikely: The ITC Evidence-Based Position

Cited by 181 publications

References 68 publications

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

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

Clinical Applications of Simultaneous PET/MR Imaging Using (R)-[11C]-Verapamil with Cyclosporin A: Preliminary Results on a Surrogate Marker of Drug-Resistant Epilepsy

Clinical CYP3A Inhibitor Alternatives to Ketoconazole, Clarithromycin and Itraconazole, Are Not Transported into the Liver by Hepatic Organic Anion Transporting Polypeptides and Organic Cation Transporter 1

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Product

Resources

About

Clinical Applications of Simultaneous PET/MR Imaging Using (R)-[¹¹C]-Verapamil with Cyclosporin A: Preliminary Results on a Surrogate Marker of Drug-Resistant Epilepsy