Novel in vitro method reveals drugs that inhibit solute transporter alpha/beta

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10.1021/acs.molpharmaceut.8b00966Metadata
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Malinen, Melina M. Kauttonen, Antti. Beaudoin, James J. Sjöstedt, Noora. Honkakoski, Paavo. Brouwer, Kim LR. (2019). Novel in vitro method reveals drugs that inhibit solute transporter alpha/beta. Molecular Pharmaceutics, 16 (1) , 238-246. 10.1021/acs.molpharmaceut.8b00966.Rights
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Abstract
Drug interactions with the organic solute transporter alpha/beta (OSTα/β) are understudied even though OSTα/β is an important transporter that is expressed in multiple human tissues including the intestine, kidneys, and liver. In this study, an in vitro method to identify novel OSTα/β inhibitors was first developed using OSTα/β-overexpressing Flp-In 293 cells. Incubation conditions were optimized using previously reported OSTα/β inhibitors. A method including a 10 min preincubation step with the test compound was used to screen for OSTα/β inhibition by 77 structurally diverse compounds and fixed-dose combinations. Seven compounds and one fixed-dose combination (100 μM final concentration) inhibited OSTα/β-mediated dehydroepiandrosterone sulfate (DHEAS) uptake by >25%. Concentration-dependent OSTα/β inhibition was evaluated for all putative inhibitors (atorvastatin, ethinylestradiol, fidaxomicin, glycochenodeoxycholate, norgestimate, troglitazone, and troglitazone sulfate). Ethinylestradiol, fidaxomicin, and troglitazone sulfate yielded a clear concentration–inhibition response with IC50 values <200 μM. Among all tested compounds, there was no clear association between physicochemical properties, the severity of hepatotoxicity, and the degree of OSTα/β inhibition. This study utilized a novel in vitro method to identify OSTα/β inhibitors and, for the first time, provided IC50 values for OSTα/β inhibition. These data provide evidence that several drugs, some of which are associated with cholestatic drug-induced liver injury, may impair the function of the OSTα/β transporter.
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basolateral efflux bile acid cholestasis drug-induced liver injury inhibition SLC51A/BLink to the original item
http://dx.doi.org/10.1021/acs.molpharmaceut.8b00966Publisher
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