Please use this identifier to cite or link to this item: doi:10.22028/D291-30907
Title: Inhibition and stimulation of the human breast cancer resistance protein as in vitro predictor of drug–drug interactions of drugs of abuse
Author(s): Wagmann, Lea
Maurer, Hans H.
Meyer, Markus R.
Language: English
Title: Archives of Toxicology
Volume: 92
Pages: 2875–2884
Publisher/Platform: Springer
Year of Publication: 2018
Free key words: Drugs of abuse
Drug–drug interactions
Mass spectrometry
DDC notations: 500 Science
540 Chemistry
570 Life sciences, biology
Publikation type: Journal Article
Abstract: Transporter-mediated drug–drug interactions (DDI) may induce adverse clinical events. As drugs of abuse (DOA) are marketed without preclinical safety studies, only very limited information about interplay with membrane transporters are available. Therefore, 13 DOA of various classes were tested for their in vitro affinity to the human breast cancer resistance protein (hBCRP), an important efflux transporter. As adenosine 5′-triphosphate (ATP) hydrolysis is crucial for hBCRP activity, adenosine 5′-diphosphate (ADP) formation was measured and used as in vitro marker for hBCRP ATPase activity. ADP quantification was performed by hydrophilic interaction liquid chromatography coupled to high-resolution tandem mass spectrometry and its amount in test compound incubations was compared to that in reference incubations using the hBCRP substrate sulfasalazine or the hBCRP inhibitor orthovanadate. If DOA caused stimulation or inhibition, further investigations such as Michaelis–Menten kinetic modeling or IC50 value determination were conducted. Among the tested DOA, seven compounds showed statistically significant hBCRP ATPase stimulation. The entactogen 3,4-BDB and the plant alkaloid mitragynine were identified as strongest stimulators. Their affinity to the hBCRP ATPase was lower than that of sulfasalazine but comparable to that of rosuvastatin, another hBCRP model substrate. Five DOA showed statistically significant hBCRP ATPase inhibition. Determination of IC50 values identified the synthetic cannabinoid receptor agonists JWH-200 and WIN 55,212-2 as the strongest inhibitors comparable to orthovanadate. The present study clearly demonstrated that tested DOA show in part high affinities to the hBCRP within the range of model substrates or inhibitors. Thus, there is a risk of hBCRP-mediated DDI, which needs to be considered in clinical settings.
DOI of the first publication: 10.1007/s00204-018-2276-y
Link to this record: urn:nbn:de:bsz:291--ds-309074
ISSN: 1432-0738
Date of registration: 20-May-2020
Faculty: M - Medizinische Fakultät
Department: M - Experimentelle und Klinische Pharmakologie und Toxikologie
Professorship: M - Prof. Dr. Markus Meyer
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