dc.contributor.author | Malinen, Melina M | |
dc.contributor.author | Kauttonen, Antti | |
dc.contributor.author | Beaudoin, James J | |
dc.contributor.author | Sjöstedt, Noora | |
dc.contributor.author | Honkakoski, Paavo | |
dc.contributor.author | Brouwer, Kim LR | |
dc.date.accessioned | 2019-02-01T12:57:18Z | |
dc.date.available | 2019-02-01T12:57:18Z | |
dc.date.issued | 2019 | |
dc.identifier.uri | https://erepo.uef.fi/handle/123456789/7407 | |
dc.description.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. | |
dc.language.iso | englanti | |
dc.publisher | American Chemical Society (ACS) | |
dc.relation.ispartofseries | Molecular Pharmaceutics | |
dc.relation.uri | http://dx.doi.org/10.1021/acs.molpharmaceut.8b00966 | |
dc.rights | In copyright 1.0 | |
dc.subject | basolateral efflux | |
dc.subject | bile acid | |
dc.subject | cholestasis | |
dc.subject | drug-induced liver injury | |
dc.subject | inhibition | |
dc.subject | SLC51A/B | |
dc.title | Novel in vitro method reveals drugs that inhibit solute transporter alpha/beta | |
dc.description.version | final draft | |
dc.contributor.department | School of Pharmacy, Activities | |
uef.solecris.id | 59939656 | en |
dc.type.publication | Tieteelliset aikakauslehtiartikkelit | |
dc.relation.doi | 10.1021/acs.molpharmaceut.8b00966 | |
dc.description.reviewstatus | peerReviewed | |
dc.format.pagerange | 238-246 | |
dc.relation.issn | 1543-8384 | |
dc.relation.issue | 1 | |
dc.relation.volume | 16 | |
dc.rights.accesslevel | openAccess | |
dc.type.okm | A1 | |
uef.solecris.openaccess | Ei | |
dc.rights.copyright | © American Chemical Society | |
dc.type.displayType | article | en |
dc.type.displayType | artikkeli | fi |
dc.rights.url | https://rightsstatements.org/page/InC/1.0/ | |