Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 15, Pages -Publisher
MDPI
DOI: 10.3390/ijms23158430
Keywords
organic cation transporter; proton-organic cation antiporter; hCMEC; D3 cells; blood-brain barrier; orphan transporter
Funding
- Deutsche Forschungsgemeinschaft [461080000]
- Open Access Publication Funds of the Gottingen University
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This study characterized the substrate spectrum of a proton-organic cation (H + OC) antiporter, which is responsible for transporting organic cations through membranes. Using hCMEC/D3 cells as a model, the researchers examined the uptake of 72 drugs and identified 37 of them as good substrates of the H + OC antiporter. Further analysis showed that the substrates had specific characteristics, such as being more hydrophobic and having a lower topological polar surface area.
Many organic cations (OCs) may be transported through membranes by a genetically still uncharacterized proton-organic cation (H + OC) antiporter. Here, we characterized an extended substrate spectrum of this antiporter. We studied the uptake of 72 drugs in hCMEC/D3 cells as a model of the human blood-brain barrier. All 72 drugs were tested with exchange transport assays and the transport of 26 of the drugs was studied in more detail concerning concentration-dependent uptake and susceptibility to specific inhibitors. According to exchange transport assays, 37 (51%) drugs were good substrates of the H + OC antiporter. From 26 drugs characterized in more detail, 23 were consistently identified as substrates of the H + OC antiporter in six different assays and transport kinetic constants could be identified with intrinsic clearances between 0.2 (ephedrine) and 201 (imipramine) mL x minute(-1) x g protein(-1). Excellent substrates of the H + OC antiporter were no substrates of organic cation transporter OCT1 and vice versa. Good substrates of the H + OC antiporter were more hydrophobic and had a lower topological polar surface area than non-substrates or OCT1 substrates. These data and further research on the H + OC antiporter may result in a better understanding of pharmacokinetics, drug-drug interactions and variations in pharmacokinetics.
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