title: Sertraline inhibits the transport of PAT1 substrates in vivo and in vitro.
abstract: OBJECTIVE
  Intestinal 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).
  
  
  METHODS
  In 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 (10 mg·kg(-1), p.o.) as a PAT1 substrate and sertraline (0-30.6 mg·kg(-1)). Gaboxadol was quantified by hydrophilic interaction chromatography followed by MS/MS detection.
  
  
  RESULTS
  Sertraline inhibited hPAT1-mediated L-[(3)H]-Pro uptake in Caco-2 cells. This interaction between sertraline and PAT1 appeared to be non-competitive. The uptake of the hSGLT1 substrate [(14)C]-α-methyl-D-glycopyranoside and the hPepT1 substrate [(14)C]-Gly-Sar in Caco-2 cells was also decreased in the presence of 0.3 mM sertraline. In rats, the administration of sertraline (0.1-10 mM, corresponding to 0.3-30.6 mg·kg(-1), p.o.) significantly reduced the maximal gaboxadol plasma concentration and AUC after its administration p.o.
  
  
  CONCLUSIONS
  Sertraline 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.
authors: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: C U
authors: CU
authors: Nielsen
authors: S
authors: S
authors: Frølund
authors: S
authors: S
authors: Abdulhadi
authors: H
authors: H
authors: Sari
authors: L
authors: L
authors: Langthaler
authors: M K
authors: MK
authors: Nøhr
authors: M A
authors: MA
authors: Kall
authors: B
authors: B
authors: Brodin
authors: R
authors: R
authors: Holm
mesh_terms: D000284:Administration, Oral; D026905:Amino Acid Transport Systems / Q000037:antagonists & inhibitors* / Q000378:metabolism; D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D018938:Caco-2 Cells; D002845:Chromatography / Q000379:methods; D004305:Dose-Response Relationship, Drug; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D007555:Isoxazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D000074011:Peptide Transporter 1; D011392:Proline / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000494:pharmacology*; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014982:Xenopus laevis
chemical_list: D026905:Amino Acid Transport Systems; D026921:Amino Acid Transport Systems, Neutral; D007555:Isoxazoles; D000074011:Peptide Transporter 1; D011392:Proline; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; D051269:Sodium-Glucose Transporter 1; D027981:Symporters; C082186:SLC15A1 protein, human; C475905:SLC36A1 protein, human; C495674:SLC5A1 protein, human; C493537:Slc36a1 protein, rat; C015542:gaboxadol
keywords: PAT1 (SLC36A1); gaboxadol; in vivo transporter; sertraline; small intestinal absorption; transporter-mediated pharmacokinetics
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