Direct automated MALDI mass spectrometry analysis of cellular transporter function: inhibition of OATP2B1 uptake by 294 drugs
OATP2B1, a member of the solute carrier (SLC) transporter family, is an important mechanism of substrate drug uptake in the intestine and liver and therefore a determinant of clinical pharmacokinetics and site of drug-drug interactions. Other SLC transporters have emerged as pharmacology targets. St...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
1 September 2020
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| In: |
Analytical chemistry
Year: 2020, Volume: 92, Issue: 17, Pages: 11851-11859 |
| ISSN: | 1520-6882 |
| DOI: | 10.1021/acs.analchem.0c02186 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1021/acs.analchem.0c02186 Verlag, lizenzpflichtig, Volltext: https://pubs.acs.org/doi/10.1021/acs.analchem.0c02186 
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| Author Notes: | Melissa S. Unger, Lena Schumacher, Thomas Enzlein, David Weigt, Maciej J. Zamek-Gliszczynski, Matthias Schwab, Anne T. Nies, Gerard Drewes, Sandra Schulz, Friedrich B.M. Reinhard, and Carsten Hopf |
| Summary: | OATP2B1, a member of the solute carrier (SLC) transporter family, is an important mechanism of substrate drug uptake in the intestine and liver and therefore a determinant of clinical pharmacokinetics and site of drug-drug interactions. Other SLC transporters have emerged as pharmacology targets. Studies of SLC transporter uptake to-date relied on radioisotope- or fluorescence-labeled reagents or low-throughput quantification of unlabeled compounds in cell lysate. In this study, we developed a cell-based MALDI MS workflow for investigation of OATP2B1 cellular uptake by optimizing the substrate, matrix, matrix-analyte ratio, and matrix application and normalization method. This workflow was automated and applied to characterize substrate transport kinetics and to test 294 top-marketed drugs for OATP2B1 inhibition and quantify inhibitory potencies necessary for extrapolation of clinical drug-drug interaction potential. Intra-assay reproducibility of this MALDI MS method was high (CV < 10%), and results agreed well (83% overlap) with previously published radioisotope assay data. Our results indicate that fast and robust MALDI MS cellular assays could emerge as a high-throughput label-free alternative for direct assessment of drug transporter function in DDIs and toxicities as well as enable drug discovery for transporters as pharmacology targets. |
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| Item Description: | Gesehen am 22.12.2025 |
| Physical Description: | Online Resource |
| ISSN: | 1520-6882 |
| DOI: | 10.1021/acs.analchem.0c02186 |