Evaluation of salicin as an antipyretic prodrug that does not cause gastric injury
Evaluation of salicin as an antipyretic prodrug that does not cause gastric injury
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DOI：
10.1055/s-2002-33792
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发表时间：
2002-08-01
期刊：
影响因子：
2.7
通讯作者：
Hattori, M
中科院分区：
文献类型：
--
作者：
Akao, T;Yoshino, T;Hattori, M
本研究比较了水杨苷（SL）、水杨苷元（SG，SL的苷元）和水杨酸（SA，SL的活性代谢产物）在大鼠体内的药代动力学和药理作用。当SL口服给药大鼠，SA出现缓慢的血浆和水平逐渐增加，在口服水杨酸钠（SANa）或SG后观察到的快速外观相反。在5 mmol/kg剂量下，口服SL不会影响无发热大鼠的直肠温度;在该剂量下，SANa和SG显著降低体温。然而，它显着减少酵母引起的发热，产生正常的体温，并完全防止发热时，同时给予酵母。即使在5 mmol/kg剂量下，SL也未诱导胃病变;相反，SANa和SG在1、2.5和5 mmol/kg剂量下以剂量依赖性方式诱导重度胃病变。在体内系统以及使用外翻大鼠空肠囊的体外系统中证实了SL的吸收不良和SA和SG的快速吸收。口服给药后1 h，在大鼠肠道中仅检测到少量SA和SG，而在给药后1 h，超过50%的SL剂量以SL和SG的形式从肠道中回收，给药后4 h，15.8%的剂量仍以SG的形式存在。当给予无菌大鼠时，19.8%的SL剂量被完整回收，主要来自盲肠，即使在治疗后4 h也未检测到SG。这些结果表明，SL是一种前药，它逐渐转运到肠道下部，被肠道细菌水解为SG，吸收后转化为SA。因此，它产生解热作用而不引起胃损伤。
Pharmacokinetic and pharmacological studies were performed to compare the antipyretic effects of salicin (SL), saligenin (SG, an aglycone of SL) and salicylic acid (SA, an active metabolite of SL) in rats. When SL was administered orally to rats, SA appeared slowly in the plasma and levels increased gradually, in contrast to the rapid appearance observed after oral administration of sodium salicylate (SANa) or SG. Orally administered SL did not affect the rectal temperatures of afebrile rats at a dose of 5 mmol/kg; at this dose, SANa and SG lowered body temperature significantly. However, it significantly reduced yeast-induced fever, producing a normal body temperature, and completely prevented fever when administered simultaneously with yeast. SL did not induce gastric lesions even at a dose of 5 mmol/kg; conversely, SANa and SG induced severe gastric lesions in a dose-dependent manner at 1, 2.5 and 5 mmol/kg. Poor absorption of SL and rapid absorption of SA and SG were confirmed in an in vivo system, as well as in an in vitro system using everted rat jejunal sacs. Only small amounts of SA and SG were detected in the intestinal tracts of rats 1 h after oral administration, whereas more than 50% of an SL dose was recovered as SL and SG from the intestinal tracts I h after treatment and 15.8% of the dose was still present as SG 4 h after administration. When given to germ-free rats, 19.8% of the SL dose was recovered intact, mainly from the cecum, and no SG was detected even at 4 h after treatment. These results indicate that SL is a prodrug which is gradually transported to the lower part of the intestine, hydrolyzed to SG by intestinal bacteria, and converted to SA after absorption. It thus produces an antipyretic action without causing gastric injury.