Drug Metabolism and Transport Capacity of Endothelial Cells, Pericytes, and Astrocytes: Implications for CNS Drug Disposition
Wilkins, H. N.; Knerler, S. A.; Warshanna, A.; Ortiz, R. C.; Haas, K.; Orsburn, B. C.; Williams, D. W.
Show abstract
Therapeutically targeting the brain requires interactions with endothelial cells, pericytes, and astrocytes at the blood brain barrier (BBB). We evaluated regional and cell-type specific drug metabolism and transport mechanisms using rhesus macaques and in vitro treatment of primary human cells. Here, we report heterogenous distribution of representative drugs, tenofovir (TFV), emtricitabine (FTC), and their active metabolites, which cerebrospinal fluid measures could not reflect. We found that all BBB cell types possessed functional drug metabolizing enzymes and transporters that promoted TFV and FTC uptake and pharmacologic activation. Pericytes and astrocytes emerged as pharmacologically dynamic cells that rivaled hepatocytes and were uniquely susceptible to modulation by disease and treatment. Together, our findings demonstrate the importance of considering the BBB as a unique pharmacologic entity, rather than viewing it as an extension of the liver, as each cell type possesses distinct drug metabolism and transport capacities that contribute to differential brain drug disposition.
Matching journals
The top 11 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity 91%
- Pre-clinical evaluation of antiviral activity of nitazoxanide against Sars-CoV-2 91%
- A point-of-care lateral flow assay for neutralising antibodies against SARS-CoV-2 90%
Similar papers in this journal
- Longitudinal characterization of circulating extracellular vesicles and small RNA during simian immunodeficiency virus infection and antiretroviral therapy 92%
- Cerebrospinal Fluid Proteomics Reveals Inflammatory Activation in Aneurysmal Subarachnoid Hemorrhage Irrespective of HIV Status 90%
- Senescence-related cytokine levels are associated with HIV-1 serostatus and persistence 89%
Similar papers in this journal
- Therapeutic assessment of targeting ASNS combined with L-Asparaginase treatment in solid tumors and investigation of resistance mechanisms 91%
- An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19 90%
- A high-content microscopy drug screening platform for regulators of the extracellular digestion of lipoprotein aggregates by macrophages 90%
Similar papers in this journal
- Persistent biofluid small molecule alterations induced by Trypanosoma cruzi infection are not restored by antiparasitic treatment 91%
- Investigating β-lactam drug targets in Mycobacterium tuberculosis using chemical probes 91%
- Cysteine reactivity profiling identifies host regulators of Mycobacterium tuberculosis replication in human macrophages 90%
Similar papers in this journal
- Distinct lipid profile, low-level inflammation and increased antioxidant defense as a signature in HIV-1 elite control status 93%
- Elovl1 inhibition reduced very long chain fatty acids in a mouse model of adrenoleukodystrophy 92%
- A novel human blood-brain barrier model reveals pericytes as critical regulators of viral neuroinvasion 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.