All Blood Brain\nBarrier Cell Types Demonstrate Capability\nto Influence Differential Tenofovir and Emtricitabine Metabolism and\nTransport in the Brain

The blood brain barrier\n(BBB) represents a significant\nobstacle\nin brain drug penetration that challenges efforts in the treatment\nof neurological disorders. Therapeutically targeting the brain requires\ninteractions with each BBB cell type, including endothelial cells,\npericytes, and astrocytes. Yet, the relative contribution of these\nBBB cell types to the mechanisms that facilitate brain drug disposition\nis not well characterized. Here, we use first-line antiretroviral\ntherapies, tenofovir (TFV) and emtricitabine (FTC), as models to investigate\nthe mechanisms of drug transport and metabolism at the BBB that may\ninfluence access of the drug to the brain. We evaluated regional and\ncell-type-specific drug metabolism and transport mechanisms using\nrhesus macaques and in vitro treatment of primary human cells. We\nreport heterogeneous distribution of TFV, FTC, and their active metabolites,\nwhich cerebrospinal fluid measures could not reflect. We found that\nall BBB cell types possessed functional drug-metabolizing enzymes\nand transporters that promoted TFV and FTC uptake and pharmacologic\nactivation. Pericytes and astrocytes emerged as pharmacologically\ndynamic cells that rival hepatocytes and were uniquely susceptible\nto modulation by disease and treatment. Together, our findings demonstrate\nthe importance of considering the BBB as a unique pharmacologic entity\nrather than viewing it as an extension of the liver, as each cell\ntype possesses distinct drug metabolism and transport capacities that\ncontribute to differential brain drug disposition. Further, our work\nhighlights pharmacologically active pathways at the BBB that may regulate\nbrain drug disposition and impact therapeutic efforts to alleviate\nneurologic disease.