Multicompartment Drug Monitoring Reveals Paired Brain-Liver Kinetics and Selective Central Nervous System Barrier Permeability in Rats
Abstract
Characterizing drug distribution to target organs is of central importance to drug discovery, especially for compounds intended to reach the central nervous system (CNS). However, the current benchmark standard measurements, based on tissue homogenate, provide limited spatial and temporal resolution. Here, we use real-time electrochemical aptamer-based (E-AB) monitoring to determine drug concentrations across specific brain regions, blood, and liver of rats after intravenous dosing. Using vancomycin and tobramycin as models, we reveal significant regional differences in brain pharmacokinetics. Vancomycin shows distinct kinetics across cortex, hippocampus, and thalamus, crossing the blood-brain barrier (BBB) but showing limited transport across the blood-cerebrospinal fluid barrier (BCSFB). Tobramycin, despite its smaller size, fails to cross either barrier. Vancomycin's liver distribution is delayed and limited, resembling its brain kinetics more than blood. These findings challenge assumptions of uniform CNS drug distribution and fast liver uptake, highlighting the need for spatially and temporally resolved pharmacokinetic assessments. Our approach enables high-resolution, in vivo profiling of drug absorption, distribution, and clearance, offering a powerful tool to inform dosing strategies and improve translational outcomes.
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