Abstract
Recently, thyrotropin-releasing hormone (TRH) has attached much attention as a potential drug for the management of various neurogic and neuropsychiatric disorders including depression, brain injury, acute spinal trauma, schizophrenia and Alzheimer's disease. However, the absolute bioavailability of TRH is very low in man (1∼2%) due to their low lipophilicity. In order to improve the intestinal absorption of TRH, we synthesized a novel lipophilic derivative of TRH (Lau-TRH) by chemical attachment of lauric acid to the N-terminal pyroglutamyl group of TRH. The permeation of TRH and Lau-TRH across the rat upper small intestine was studied using an in vitro modified everted gut technique. Lau-TRH was more permeable than TRH in the rat upper small intestine and most of Lau-TRH were converted to TRH during permeation across the rat upper small intestine. In addition, Lau-TRH was gradually converted to TRH in mucosal side. Furthermore, the acylation of TRH with lauric acid was more effective than the absorption enhancers such as EDTA, sodium caprate, and lauryl maltoside in enhancing the upper small intestinal absorption of TRH. These results indicated that chemical modification of TRH with fatty acid might be a useful approach for improving the upper small intestinal transport of TRH.
