Development of a Novel Tool To Demystify Drug Distribution at Tissue‐Blood Barriers

Tissue endothelial cells express ABC‐transporter enzymes that change the concentration of small molecules within different tissue compartments. These “blood‐tissue barriers” have been shown to directly affect the efficacy and toxicity of anticancer, antimicrobial, psychiatric, and anti‐epileptic drugs. Currently this phenomenon is best studied for the blood‐brain barrier, but remains enigmatic for most other tissues. In addition, canonical pharmacokinetic theory specifically assumes an equal concentration of free drug within all tissue compartments. Inspired by Lipinski's “rule of 5,” we here clarify current knowledge on drug–tissue distribution by: 1) curating the in‐vivo literature on 73 drugs across 23 tissues and 2) developing two graphical web‐based applications to visually describe and interpret data. These curated in‐vivo dataset and visualization tools enabled us to achieve new insights into the logic of the barrier‐tissue organization and showed remarkable correspondence to whole‐body imaging of radiolabeled molecules. Blood‐tissue barriers directly affect the efficacy and toxicity of small‐molecule drugs, and yet the chemical logic of these barriers remains largely enigmatic. Here we curate/reconcile in‐vivo literature data on 73 drugs across four mouse models of barrier function. This dataset enables visualization and computational analyses on the tissue‐distribution of clinical drugs.