Improvement of intestinal absorption of thyrotropin-releasing hormone by chemical modification with lauric acid.
Intestinal absorption of 125I-labelled lauryl thyrotropin-releasing hormone (Lau-TRH), a novel lipophilic derivative of TRH, was examined by rat in-situ closed intestinal loops. At a dose of 1 mumol per rat into the small intestine, a significant increase in percent of dose in plasma radioactivity of Lau-TRH was observed in comparison with that of TRH. A dose-dependent decrease in percent of dose in plasma radioactivity of TRH was noted, suggesting a saturable process of TRH transport. In contrast, the percent of dose in plasma radioactivity of Lau-TRH increased with increasing dose of Lau-TRH. The stability of TRH and Lau-TRH was studied in plasma and rat small intestinal homogenates. Lau-TRH was more stable than TRH in rat plasma. These results suggest that chemical modification of TRH with lauric acid may not only increase the lipophilicity of TRH but also reduce the degradation of TRH, resulting in the increased plasma radioactivity of TRH. On the other hand, Lau-TRH was gradually converted to TRH in the intestinal mucosal homogenate. These findings indicate that chemical modification of TRH with lauric acid might be a useful approach for improving the intestinal absorption of this peptide.
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Japan.
K
K
Yamada
M
M
Murakami
A
A
Yamamoto
K
K
Takada
S
S
Muranishi
D000818:Animals; D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D007848:Laurates / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics*
D007848:Laurates; D013973:Thyrotropin-Releasing Hormone