Enhancement of intestinal transport of thyrotropin-releasing hormone via a carrier-mediated transport system by chemical modification with lauric acid.
The transport characteristics of thyrotropin-releasing hormone (TRH) and its chemically modified derivative with lauric acid (Lau-TRH) across the rat small or large intestine were estimated by means of an in vitro everted sac experiment. Both compounds were especially absorbed from the upper small intestine. The penetration of TRH across the upper small intestine was significantly increased by conjugation with lauric acid. Lau-TRH administered to the mucosal side appeared as a native TRH form in the serosal side. On the other hand, a temperature dependency and a directional difference in the transfer rates of these compounds were observed in the everted and non-everted sacs of the upper small intestine. Moreover, the penetration of TRH and Lau-TRH across the upper small intestine was inhibited by 0.25 mM 2,4-dinitrophenol and 10 mM glycylglycine. In addition, Lau-TRH was very stable in the cytosolic fraction of the small intestinal mucosa, while it was gradually converted to the native TRH in the brush-border membrane (BBM) fraction. The binding amounts of TRH to the BBM were remarkably enhanced by the lauric acid conjugation; however, its binding was nonspecific. Therefore, it was suggested that Lau-TRH rapidly bound to the BBM in the small intestine, where Lau-TRH is converted to TRH, and this released TRH is efficiently transported by an oligopeptide transporter which exists in the upper small intestine.
Tanaka
K
K
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Japan.
Fujita
T
T
Yamamoto
Y
Y
Murakami
M
M
Yamamoto
A
A
Muranishi
S
S
D019297:2,4-Dinitrophenol; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D004140:Dinitrophenols / Q000494:pharmacology; D004355:Drug Stability; D006033:Glycylglycine / Q000494:pharmacology; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000378:metabolism; D007850:Lauric Acids / Q000494:pharmacology*; D008297:Male; D008871:Microvilli / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013973:Thyrotropin-Releasing Hormone / Q000737:chemistry* / Q000378:metabolism*
D002352:Carrier Proteins; D004140:Dinitrophenols; D007850:Lauric Acids; D006033:Glycylglycine; C030358:lauric acid; D013973:Thyrotropin-Releasing Hormone; D019297:2,4-Dinitrophenol