Endogenous Probes for Drug Transporters: Balancing Vision With Reality

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In the early 1990s, the pharmaceutical industry expanded the use of in vitro methods, leveraging human‐derived reagents and the application of automation, and so attention quickly turned to high‐throughput screening (“ADME‐HTS”).1 Similar progress supported greater use of computer‐assisted databases, data visualization tools, building of structure–activity relationships (“ADME SAR”), modeling and simulation (M&S)‐based in vitro‐in vivo extrapolations (IVIVEs), and human PK‐ADME‐DDI projections.2 In response, a wide array of tools and innovative solutions were developed to support clinical phenotyping and drug–drug interaction (DDI) assessment enabled by drug probes specific for individual drug‐metabolizing enzymes and some transporters, drug probe cocktails, micro‐dosing, saliva analysis, blood spot analysis, and imaging agents (Figure1).5 More recently, PK‐ADME‐DDI science has been influenced by “translational science,” “precision medicine,” pharmacometrics, epigenetics, “omics” (e.g., pharmacogenomics, metabolomics), and systems biology.14
From an industrial standpoint, the goal has always been to support the clinical advancement of novel chemical entities (NCEs) with the desired “target” PK‐ADME‐DDI profile; optimal PK properties and lower dose (low peak‐to‐trough plasma concentration ratio, linear‐dose dependency, suitable plasma half‐life (t1/2), good absorption, and minimal first‐pass effect), appropriate therapeutic index for the target indication, minimal impact of drug‐metabolizing enzyme and transporter genotype on PK, and reduced DDI potential as perpetrator and victim. Therefore, it is not surprising that numerous researchers have sought to identify endogenous probes (“biomarkers”) for various drug‐metabolizing enzymes (e.g., cytochrome P450 3A4) and transporters (e.g., organic cation transporter 2 (OCT2), multidrug and toxin extrusion protein 1 (MATE1), organic anion transporter 3 (OAT3), and organic anion transporting polypeptides (OATPs)) in an effort to facilitate clinical phenotyping and DDI assessment.7
The following review will summarize currently available endogenous probes for different transporters, the pros and cons, challenges, opportunities, considerations (e.g., kinetics, dynamic range, and specificity), and performance. It is concluded that the existing menu of available tools needs to be expanded, that existing endogenous probes need further characterization and validation, and that widely used commercial M&S packages need to be updated to support modeling of endogenous marker PK‐ADME‐DDI profiles. Although the potential utility of endogenous probes is great, it is worth noting that vastly improved analytical methods do enable some well‐characterized drug probes (individually or as cocktails) to be administered at “subtherapeutic”—generally regarded as safe (“GRAS”)—doses (not necessarily “nano” or “micro” doses).6 In the future, it is likely that transporter phenotyping and DDI assessment in the clinic will leverage various combinations of probes (drug and endogenous).6 For a given NCE, it is envisioned that the choice of the most appropriate endogenous‐drug probe combination will be informed by fully integrated in vitro data packages, with a focus on the combinations of enzymes and transporters that present the greatest DDI risk.
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