Evaluation of salicin as an antipyretic prodrug that does not cause gastric injury

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.