Commentary on: “Influence of OATP1B1 Function on the Disposition of Sorafenib‐β‐D‐Glucuronide”

Approaches to predict and characterize drug–drug interactions (DDI) mediated by a single drug-metabolizing enzyme or a single transporter are well established. However, complex DDIs, where multiple metabolic and transport processes are involved, require an integrative translational approach.1,2 If a drug undergoes reversible metabolism, the net contribution of the processes of metabolism, uptake, and/or efflux transport on drug disposition and response is difficult to deconvolute and is particularly important for narrow therapeutic index drugs. The importance of the interplay between drug transporter(s) and drug metabolizing enzyme(s) on the processes of drug absorption, distribution, and metabolism was realized over 20 years ago.3 Since then, numerous investigations have elucidated the impact of transporter-mediated tissue distribution on metabolite formation and its consequential effect on drug safety and efficacy. Recent studies, fueled by the knowledge of the role transporters play in DDIs, have enhanced our understanding of the clinical significance of transporter–metabolism interplay, where the metabolites themselves are victims and perpetrators of transporter-mediated DDIs. An excellent example of this is highlighted in the article “Influence of OATP1B1 function on the disposition of sorafenib-β-D-glucuronide” by Bins et al.4 This eloquent bench-to-bedside investigation builds upon previous mechanistic studies5 by evaluating the clinical significance of inhibiting OATP1B1-mediated transport of the glucuronide metabolite of sorafenib, sorafenib-β-Dglucuronide (SG). This study is particularly unique, since SG demonstrates a novel and circuitous route of elimination called “hepatocyte-hopping,” whereby after SG formation in the hepatocyte, SG can undergo sinusoidal efflux via ABCC3 and is actively taken up by neighboring hepatocytes via OATP1B1/OATP1B3.6 In Bins et al., through the use of in vitro transporter assays and mouse models, the authors demonstrate that SG is a substrate of mouse Oatp1b2 and human OATP1B1, and its uptake into liver cells is inhibited by rifampin, resulting in enhanced SG concentrations in plasma and a 90% reduction of the liver-to-plasma ratio of SG in mice. In addition, in a clinical DDI study evaluating the concomitant administration of sorafinib with rifampin in cancer