title: 5-Hydroxy-L-tryptophan alters gaboxadol pharmacokinetics in rats: involvement of PAT1 and rOat1 in gaboxadol absorption and elimination.
abstract: The aim was to investigate the effect of 5-hydroxy-L-tryptophan (5-HTP) on gaboxadol pharmacokinetics in rats. As both 5-HTP and gaboxadol bind to the human proton-coupled amino acid transporter, hPAT1, a drug-drug interaction at the level of intestinal absorption might occur. The in vitro transport of gaboxadol was measured across the hPAT1-expressing cell line Caco-2, and via the rat organic anion transporter, rOat1, in Xenopus oocytes pre-injected with rOat1 cRNA. The in vivo pharmacokinetic profile of gaboxadol after oral administration to rats was investigated in the absence and presence of a pre-dose of 5-HTP. In Caco-2 cell monolayers >80% of the absorptive gaboxadol transport was suggested to be hPAT1-mediated. In rats, the initial absorption rate of gaboxadol was decreased in the presence of 5-HTP. The AUC of gaboxadol was increased by a factor of 3.6-5.5 when rats were pre-dosed with 5-HTP. Gaboxadol was a substrate for the renal transporter rOat1 with a K(m)-value of 151 microM. 5-HTP did not interact with rOat1. In conclusion, gaboxadol acts as a substrate for hPAT1 and is a substrate of rOat1. In rats, 5-HTP decreased the initial absorption rate and increased AUC of gaboxadol. 5-HTP thus had a significant impact on the pharmacokinetic profile of gaboxadol.
authors.affiliation: Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Mie
authors.initials: M
authors.lastname: Larsen
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.forename: Klaus Gjervig
authors.initials: KG
authors.lastname: Jensen
authors.forename: Christina
authors.initials: C
authors.lastname: Sveigaard
authors.forename: Birger
authors.initials: B
authors.lastname: Brodin
authors.forename: Carsten Uhd
authors.initials: CU
authors.lastname: Nielsen
mesh_terms: D006916:5-Hydroxytryptophan / Q000009:adverse effects*; D026905:Amino Acid Transport Systems / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D004347:Drug Interactions; D005746:Gastric Emptying / Q000187:drug effects; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007555:Isoxazoles / Q000493:pharmacokinetics*; D007700:Kinetics; D008297:Male; D009865:Oocytes / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D026905:Amino Acid Transport Systems; D007555:Isoxazoles; D027362:Organic Anion Transport Protein 1; C475905:SLC36A1 protein, human; C421043:Slc22a6 protein, rat; D027981:Symporters; D006916:5-Hydroxytryptophan; C015542:gaboxadol