Extracellular vesicles as xenobiotic-metabolizing enzyme carriers: a new paradigm for brain drug metabolism

Emerging evidence suggests hepatocyte-derived extracellular vesicles (hd-EVs) may transport drug-metabolizing enzymes across the BBB. This liver-brain metabolic axis remains a conceptual model that requires in vivo validation of localized brain metabolism following EV transfer. The traditional liver-centric paradigm cannot fully explain CNS-specific drug effects, such as phenytoin induced neurotoxicity and acetaminophen-linked neuroinflammation, which occur without substantial brain drug accumulation. We propose that EVs function as systemic metabolic shuttles, transporting catalytically active xenobiotic metabolizing enzymes (XMEs), including cytochrome P450s, UDP glucuronosyltransferases, and glutathione S-transferases from hepatic tissues across the BBB to enable localized drug metabolism within the CNS. Circulating EVs can carry xenobiotic-metabolizing enzymes that retain catalytic activity, and their cargo appears to be modulated by hepatic stress and drug exposure. Some studies also suggest that EVs are capable of crossing the BBB via receptor-mediated endocytosis and being internalized by brain cells. Critical limitations remain in demonstrating direct catalytic activity of EV delivered enzymes within brain resident cells and understanding the molecular mechanisms governing enzyme cargo selection and brain specific targeting. If confirmed, EV-mediated XME transport has the potential to transform neuropharmacology by reframing the brain as a metabolically active organ supported by systemic vesicle communication. This review details the justification for this new theory as well as potential testing methods.