Substrates of the Human Brain Proton-Organic Cation Antiporter and Comparison with Organic Cation Transporter 1 Activities
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 bloo...
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| Format: | Article |
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MDPI AG
2022-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/15/8430 |
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| author | David A. Doetsch Salim Ansari Ole Jensen Lukas Gebauer Christof Dücker Jürgen Brockmöller Alexandra Sachkova |
| author_facet | David A. Doetsch Salim Ansari Ole Jensen Lukas Gebauer Christof Dücker Jürgen Brockmöller Alexandra Sachkova |
| author_sort | David A. Doetsch |
| collection | DOAJ |
| description | 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 × minute<sup>−1</sup> × g protein<sup>−1</sup>. 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. |
| first_indexed | 2024-03-09T10:08:28Z |
| format | Article |
| id | doaj.art-44d03a538c3348d984624174864b051f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T10:08:28Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-44d03a538c3348d984624174864b051f2023-12-01T22:57:33ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012315843010.3390/ijms23158430Substrates of the Human Brain Proton-Organic Cation Antiporter and Comparison with Organic Cation Transporter 1 ActivitiesDavid A. Doetsch0Salim Ansari1Ole Jensen2Lukas Gebauer3Christof Dücker4Jürgen Brockmöller5Alexandra Sachkova6Institute of Clinical Pharmacology, University Medical Center, Georg-August University, Robert-Koch-Str. 40, 37075 Göttingen, GermanyInstitute of Clinical Pharmacology, University Medical Center, Georg-August University, Robert-Koch-Str. 40, 37075 Göttingen, GermanyInstitute of Clinical Pharmacology, University Medical Center, Georg-August University, Robert-Koch-Str. 40, 37075 Göttingen, GermanyInstitute of Clinical Pharmacology, University Medical Center, Georg-August University, Robert-Koch-Str. 40, 37075 Göttingen, GermanyInstitute of Clinical Pharmacology, University Medical Center, Georg-August University, Robert-Koch-Str. 40, 37075 Göttingen, GermanyInstitute of Clinical Pharmacology, University Medical Center, Georg-August University, Robert-Koch-Str. 40, 37075 Göttingen, GermanyInstitute of Clinical Pharmacology, University Medical Center, Georg-August University, Robert-Koch-Str. 40, 37075 Göttingen, GermanyMany 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 × minute<sup>−1</sup> × g protein<sup>−1</sup>. 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.https://www.mdpi.com/1422-0067/23/15/8430organic cation transporterproton-organic cation antiporterhCMEC/D3 cellsblood–brain barrierorphan transporter |
| spellingShingle | David A. Doetsch Salim Ansari Ole Jensen Lukas Gebauer Christof Dücker Jürgen Brockmöller Alexandra Sachkova Substrates of the Human Brain Proton-Organic Cation Antiporter and Comparison with Organic Cation Transporter 1 Activities International Journal of Molecular Sciences organic cation transporter proton-organic cation antiporter hCMEC/D3 cells blood–brain barrier orphan transporter |
| title | Substrates of the Human Brain Proton-Organic Cation Antiporter and Comparison with Organic Cation Transporter 1 Activities |
| title_full | Substrates of the Human Brain Proton-Organic Cation Antiporter and Comparison with Organic Cation Transporter 1 Activities |
| title_fullStr | Substrates of the Human Brain Proton-Organic Cation Antiporter and Comparison with Organic Cation Transporter 1 Activities |
| title_full_unstemmed | Substrates of the Human Brain Proton-Organic Cation Antiporter and Comparison with Organic Cation Transporter 1 Activities |
| title_short | Substrates of the Human Brain Proton-Organic Cation Antiporter and Comparison with Organic Cation Transporter 1 Activities |
| title_sort | substrates of the human brain proton organic cation antiporter and comparison with organic cation transporter 1 activities |
| topic | organic cation transporter proton-organic cation antiporter hCMEC/D3 cells blood–brain barrier orphan transporter |
| url | https://www.mdpi.com/1422-0067/23/15/8430 |
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