5-Hydroxy-l-tryptophan alters gaboxadol pharmacokinetics in rats: Involvement of PAT1 and rOat1 in gaboxadol absorption and elimination

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 Km-value of 151 μM. 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.