含絲胺酸及色胺酸之Cefuroxime先驅藥的合成及安定性研究   全文下載

Synthesis and Stability Studies on a Tripartite Prodrug of Cefuroxime

Cefuroxime為臨床上廣為使用之β-lactam類抗生素，然其缺點為口服生體可用率低，僅能打針。加上其體內分布體積小、腎臟清除率高，致體內半衰期為1.1小時。本研究以研發可口服吸收之Cefuroxime先驅藥為目標，設計合成一含有絲胺酸及色胺酸之三元式先驅藥1。期以先驅藥之脂溶性增加而成為口服劑型，並藉由色胺酸之高蛋白吸附力而減緩Cefuroxime腎臟清除速率。化合物1之合成係由色胺酸與絲胺酸接合之雙胜?3藉由絲胺酸雙胜肱之-OH基接到Cefuroxime之4-COOH基形成酯類先驅藥。先驅藥1在pH 6.5及pH 7 .4磷酸緩衝溶液中陣搖90分鐘後，分別只有1.6%及23%分解。化合物1在以離體大鼠小腸製備之腸膜中培養2.5小時後，仍可偵測到60%。此化合物在模擬腸液中之安定性將作為我們進一步測試該藥生體可用率以及評估其作為Cefuroxime口服先驅藥之基礎。

N-Cbz-tryptophan was attached to cefuroxime at its 4-COOH via L-serine methyl ester to form compound 1. This compound is designed as a tripartite prodrug of cefuroxime for oral use. The compound was stable in pH 6.5 and pH 7.4 phosphate buffer solutions. Sixty percent of this compound remained intact after incubation in a mucosal suspension prepared from rat intestine at 37°C for 2.5 hr. The stability of this compound toward intestinal degradation indicated that it might be feasible as an oral prodrug of cefuroxime. Oral bioavailability in terms of the prodrug and the released parent drug is currently being investigated. Cefuroxime為臨床上廣為使用之β-lactam類抗生素，然其缺點為口服生體可用率低，僅能打針。加上其體內分布體積小、腎臟清除率高，致體內半衰期為1.1小時。本研究以研發可口服吸收之Cefuroxime先驅藥為目標，設計合成一含有絲胺酸及色胺酸之三元式先驅藥1。期以先驅藥之脂溶性增加而成為口服劑型，並藉由色胺酸之高蛋白吸附力而減緩Cefuroxime腎臟清除速率。化合物1之合成係由色胺酸與絲胺酸接合之雙胜肽3藉由絲胺酸雙胜肱之-OH基接到Cefuroxime之4-COOH基形成酯類先驅藥。先驅藥1在pH 6.5及pH 7 .4磷酸緩衝溶液中陣搖90分鐘後，分別只有1.6%及23%分解。化合物1在以離體大鼠小腸製備之腸膜中培養2.5小時後，仍可偵測到60%。此化合物在模擬腸液中之安定性將作為我們進一步測試該藥生體可用率以及評估其作為Cefuroxime口服先驅藥之基礎。