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Dissecting Complex Drug-Drug Interactions

In a recent paper published in Clinical and Translational Science (CTS) entitled “Influence of OATP1B1 Function on the Disposition of Sorafenib-beta-D-Glucuronide”, Bins and colleagues employed a comprehensive experimental approach to investigate the contribution of OATP1B1 in the hepatocellular disposition of sorafenib. This paper is important and impactful for multiple reasons. First, while the approaches are well defined to predict simple drug-drug interactions, the optimal strategy to characterize complex drug-drug interactions continues to evolve; and the work by Bins and colleagues represents an excellent “bench-to-bedside” approach case example in which a broad range of experimental approaches, including in vitro studies and in vivo preclinical and clinical studies, were used to gain significant insights into the hepatocellular handling of sorafenib. Second, the work of Bins and colleagues is unique since it helps elucidate the circuitous elimination process of Sorafenib-beta-D-Glucuronide (SG), a novel process referred to as “hepatocyte-hopping”. Third, the findings reported in the paper highlight the importance of considering the hepatic processing of glucuronides for drugs that undergo extensive phase II metabolism.

In addition, the work by Bins and colleagues points to several key areas worthy of future investigation. For example, further characterization of the relationship between SG exposure and sorafenib adverse events may provide insights on how to optimally guide the use of OATP1B1 inhibitors in cancer patients treated with sorafenib.

As noted in the accompanying commentary by Drs. Kari Morrissey, Les Benet, and Joe Ware, “defining … intertwined [metabolic and transporter] processes is a tremendous opportunity for clinical and translational scientists to explore, particularly in determining whether these findings are broadly applicable to other drugs. Through understanding the dual role of complex DDIs and patient-specific covariates (e.g., genetics, comorbidities) on drug response, individualized therapy to maximize therapeutic benefit can be achieved”. The CTS editorial team welcomes the submission of robust, translational research of complex drug-drug interactions such as the work by Bins and colleagues.

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