L-Dopa-D-phenylglycine之合成及小腸吸收   全文下載

Preparation and Intestinal Absorption of L-Dopa-D-phenylglycine

本研究合成雙胜?L-dopa-D-phenylglycine，作為dopamine之前驅藥。設計原理為以D-phenylglycine作為藥引子，導引L-dopa透過小腸小胜?運輸體（oligopeptide transporter, PepTl）吸收。我們由大鼠小腸黏膜製作刷狀緣膜包囊（brush border membrane vesicle, BBMV），藉由L-dopa-D-phenylglycine與L-Gly-L-Pro, L-Gly-L-Phe及cephradine對PepTl的競爭，測量其BBMV之吸收量，探討L-dopa-D-phenylglycine是否透過小腸小胜?運輸體吸收。在雙胜?L-Gly-L-Pro, L-Gly-L-Phe及擬三胜?cephradine的存在下，L-dopa-D-phenylglycine在BBMV之吸收分別降為54.1 ± 4.5%, 57.6 ± 5.2%及62.9 ± 10.2%，胺基酸L-Phe則不影響其吸收，顯示L-dopa-D-phenylglycine可透過小腸小胜?運輸體吸收。在活體Wistar大鼠進行空腸灌流試驗達到血中濃度恆定時，L-dopa-D-phenylglycine的血中濃度（104.0 ± 12.9μg／mL）以當量數計為L-dopa血中濃度（1.24μg／mL）的50.1倍，顯示L-dopa-D-Phenylglycine在大鼠小腸具有優於L-dopa的吸收。這個雙胜?前驅藥在大鼠的吸收動力學研究證明D-Phenylglycine具有藥引子功能，可促進L-dopa藉由小腸PepTl吸收。"

L-Dopa-D-phenylglycine was synthesized in this laboratory as L-dopa derivative for improving its intestinal absorption. As designed for transport through the intestine via oligopeptide transporter (PepT1), the competition of this dipeptide with known substrates for PepT1 in brush-border membrane vesicle (BBMV) was investigated. At the presence of L-Glycinyl-L-proline (L-Gly-L-Pro), L-Glycinyl-Lphenylalanine (L-Gly-L-Phe) or cephradine, the uptake of L-dopa-D-phenylglycine in BBMV was reduced to 54.1 ± 4.5%, 57.6 ± 5.2% or 62.9 ± 10.2%, respectively. The inhibition by these dipeptides and the tripeptide mimetic amino-β-lactam was significantly higher than by amino acids L-Phenylalanine (L-Phe) or L-dopa. The results suggested that the intestinal H+-coupled PepT1 was involved in the uptake of L-dopa-D-phenylglycine. The steady state plasma concentrations of L-dopa-D-phenylglycine and L-dopa in rats after a single pass in-situ jejunal perfusion with 0.1 mM perfusate were 104.0 ± 12.90 μg/mL and 1.24 μg/mL respectively. L-Dopa-D-phenylglycine demonstrated a 50.1 fold higher plasma concentration, in terms of molar ratio, than that of L-dopa. D-Phenylglycine was proved to be a satisfactory moiety for the improvement of L-dopa absorption in the intestine. 本研究合成雙胜肽L-dopa-D-phenylglycine，作為dopamine之前驅藥。設計原理為以D-phenylglycine作為藥引子，導引L-dopa透過小腸小胜肽運輸體（oligopeptide transporter, PepTl）吸收。我們由大鼠小腸黏膜製作刷狀緣膜包囊（brush border membrane vesicle, BBMV），藉由L-dopa-D-phenylglycine與L-Gly-L-Pro, L-Gly-L-Phe及cephradine對PepTl的競爭，測量其BBMV之吸收量，探討L-dopa-D-phenylglycine是否透過小腸小胜肽運輸體吸收。在雙胜肽L-Gly-L-Pro, L-Gly-L-Phe及擬三胜肽cephradine的存在下，L-dopa-D-phenylglycine在BBMV之吸收分別降為54.1 ± 4.5%, 57.6 ± 5.2%及62.9 ± 10.2%，胺基酸L-Phe則不影響其吸收，顯示L-dopa-D-phenylglycine可透過小腸小胜肽運輸體吸收。在活體Wistar大鼠進行空腸灌流試驗達到血中濃度恆定時，L-dopa-D-phenylglycine的血中濃度（104.0 ± 12.9μg／mL）以當量數計為L-dopa血中濃度（1.24μg／mL）的50.1倍，顯示L-dopa-D-Phenylglycine在大鼠小腸具有優於L-dopa的吸收。這個雙胜肽前驅藥在大鼠的吸收動力學研究證明D-Phenylglycine具有藥引子功能，可促進L-dopa藉由小腸PepTl吸收。