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

Area of Science:

• Pharmacology
• Biochemistry
• Physiology

Background:

• Tissue endothelial cells express ABC-transporter enzymes, creating blood-tissue barriers that influence small molecule concentrations.
• These barriers affect the efficacy and toxicity of various drugs, including anticancer, antimicrobial, psychiatric, and anti-epileptic medications.
• Current pharmacokinetic theory often assumes equal free drug concentrations across all tissue compartments, which may not reflect reality.

Purpose of the Study:

• To curate existing in-vivo literature on drug distribution across 23 tissues for 73 different drugs.
• To develop user-friendly, graphical web-based applications for visualizing and interpreting drug-tissue distribution data.
• To gain new insights into the logic governing blood-tissue barrier organization and its impact on pharmacokinetics.

Main Methods:

• Comprehensive literature review and curation of in-vivo data for 73 drugs across 23 distinct tissues.
• Development of two interactive, graphical web-based applications for data visualization and interpretation.
• Analysis of curated data to identify patterns and principles of drug distribution influenced by tissue barriers.

Main Results:

• A curated in-vivo dataset detailing drug distribution across multiple tissues was established.
• Novel visualization tools were created, enabling clearer interpretation of complex drug distribution data.
• The study revealed significant insights into blood-tissue barrier organization, aligning with whole-body imaging of radiolabeled molecules.

Conclusions:

• The curated dataset and visualization tools provide a valuable resource for understanding drug-tissue distribution.
• New insights into the logic of barrier-tissue organization challenge canonical pharmacokinetic assumptions.
• This work has implications for optimizing drug efficacy and minimizing toxicity by considering barrier effects.