期刊
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
卷 39, 期 1-3, 页码 68-75出版社
ELSEVIER
DOI: 10.1016/j.ejps.2009.10.013
关键词
In vivo absorption; hPAT1(SLC36A1); rOat1 (Slc22a6); Gaboxadol; 5-Hydroxy-L-tryprophan (5-HTP)
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 mu M. 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. (C) 2009 Elsevier B.V. All rights reserved.
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