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Recent analyses demonstrated that metabolites are unlikely to contribute significantly to clinical inhibition of cytochrome P450 (P450)– mediated drug metabolism, and that only ∼2% of this type of drug interaction could not be predicted from the parent drug alone. Due to generally increased polarity and decreased permeability, metabolites are less likely to interact with P450s, but their disposition is instead more likely to involve transporters. This commentary presents case studies illustrating the potential importance of transporters as determinants of metabolite disposition, and as sites of drug interactions, which may alter drug efficacy and safety. Many of these examples are hydrophilic phase II conjugates involved in enterohepatic cycling, where modulation of transporter-dependent disposition may alter pharmacokinetics/pharmacodynamics. The case studies suggest that characterization of metabolite disposition, toxicology, and pharmacology should not focus solely on metabolites with appreciable systemic exposure, but should take into consideration major excretory metabolites. A more thorough understanding of metabolite (phase I and II; circulating and excreted) transport properties during drug development may provide an improved understanding of complex drug-drug interactions (DDIs) that can alter drug and/or metabolite systemic and intracellular exposure. Knowledge and capability gaps remain in clinical translation of in vitro and animal data regarding metabolite disposition. To this end, useful experimental and modeling approaches are highlighted. Application of these tools may lead to a better understanding of metabolite victim and perpetrator DDI potential, and ultimately the establishment of approaches for prediction of pharmacodynamic and toxicodynamic consequences of metabolite transport modulation. Introduction Preface. There has been a longstanding concern that metabolites may contribute to drug-drug interactions (DDIs) or toxicity by modulating drug-metabolizing enzymes and/or transporters (perpetrator DDIs) or through comedications altering metabolite disposition (victim DDIs). Recent reviews of public domain data concluded that metabolites rarely perpetrate clinical DDIs via inhibition of cytochrome P450 (P450) enzymes (Yeung et al., 2011). A review of 129 clinical P450-inhibitor drugs reported that only 2% (amiodarone, bupropion, and sertraline) were identified as perpetrators of clinical DDIs that could not be predicted without consideration of metabolites (Yeung et al., 2011). Metabolites are unlikely to cause clinical P450mediated DDIs generally due to increased polarity and metabolic stability. However, these properties, together with reduced passive permeability, render metabolites more susceptible to interactions with drug transporters (Zamek-Gliszczynski et al., 2006a; Benet, 2010; Smith and Dalvie, 2012; Loi et al., 2013) (Fig. 1; Table 1). The concern of metabolites as both victims and perpetrators of transporter-based DDIs has been highlighted in recent DDI guidance and the International Transporter Consortium white paper (Zamek-Gliszczynski et al., 2013b). This commentary presents a case for a greater understanding of metabolite transport properties considering the increased likelihood of transporter-based relative to P450-based metabolite interactions. A summary of current regulatory positions on metabolite characterization is provided in the initial section, as a starting point for drug development teams to create project-specific strategies, and is followed by an overview of key transporters interacting with drug metabolites. A series of diverse case studies follows, highlighting scenarios when alteration of transporter-mediated disposition of a metabolite (victim) or dx.doi.org/10.1124/dmd.113.055558. ABBREVIATIONS: BCRP, breast cancer resistance protein; BSEP, bile salt export pump; CNS, central nervous system; DDI, drug-drug interaction; GSK1325756, N-(4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl)-N9-(3-fluoro-2-methylphenyl)urea; HEK, human embryonic kidney; MRP, multidrug resistance-associated protein; MSI, mass spectrometry imaging; LY2090314, 3-[9-fluoro-2-(piperidin-1-ylcarbonyl)-1,2,3,4-tetrahydro[1,4]diazepino [6,7,1-hi]indol-7-yl]-4-imidazo[1,2-a]pyridin-3-yl-1H-pyrrole-2,5-dione; OAT, organic anion transporter; OATP, organic anion transporting polypeptide; P450, cytochrome P450; PBPK, physiologically based pharmacokinetic; P-gp, P-glycoprotein; TR, Mrp2-deficient; UGT, UDP-glucuronosyltransferase. 650 at A PE T Jornals on A ril 4, 2017 dm d.aspurnals.org D ow nladed from