4.7 Article

Sertraline inhibits the transport of PAT1 substrates in vivo and in vitro

期刊

BRITISH JOURNAL OF PHARMACOLOGY
卷 170, 期 5, 页码 1041-1052

出版社

WILEY
DOI: 10.1111/bph.12341

关键词

PAT1 (SLC36A1); gaboxadol; sertraline; small intestinal absorption; in vivo transporter; transporter-mediated pharmacokinetics

资金

  1. Carlsberg Foundation

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Background and PurposeIntestinal nutrient transporters may mediate the uptake of drugs. The aim of this study was to investigate whether sertraline interacts with the intestinal proton-coupled amino acid transporter 1 PAT1 (SLC36A1). Experimental ApproachIn vitro investigations of interactions between sertraline and human (h)PAT1, hSGLT1 (sodium-glucose linked transporter 1) and hPepT1 (proton-coupled di-/tri-peptide transporter 1) were conducted in Caco-2 cells using radiolabelled substrates. In vivo pharmacokinetic investigations were conducted in male Sprague-Dawley rats using gaboxadol (10mg center dot kg(-1), p.o.) as a PAT1 substrate and sertraline (0-30.6mg center dot kg(-1)). Gaboxadol was quantified by hydrophilic interaction chromatography followed by MS/MS detection. Key ResultsSertraline inhibited hPAT1-mediated L-[H-3]-Pro uptake in Caco-2 cells. This interaction between sertraline and PAT1 appeared to be non-competitive. The uptake of the hSGLT1 substrate [C-14]--methyl-D-glycopyranoside and the hPepT1 substrate [C-14]-Gly-Sar in Caco-2 cells was also decreased in the presence of 0.3mM sertraline. In rats, the administration of sertraline (0.1-10mM, corresponding to 0.3-30.6mg center dot kg(-1), p.o.) significantly reduced the maximal gaboxadol plasma concentration and AUC after its administration p.o. Conclusions and ImplicationsSertraline is an apparent non-competitive inhibitor of hPAT1-mediated transport in vitro. This inhibitory effect of sertraline is not specific to hPAT1 as substrate transport via hPepT1 and hSGLT1 was also reduced in the presence of sertraline. In vivo, sertraline reduced the amount of gaboxadol absorbed, suggesting that the inhibitory effect of sertraline on PAT1 occurs both in vitro and in vivo. Hence, sertraline could alter the bioavailability of drugs absorbed via PAT1.

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