HYDROLYSIS OF SALICYLIC-ACID TYROSINE AND SALICYLIC-ACID METHIONINE PRODRUGS IN THE RABBIT

We examined the hydrolysis of salicylic acid-tyrosine (salicyl-tyrosine) and salicylic acid-methionine (salicyl-methionine) conjugates following oral, intravenous, intracecal and rectal administration (434, 72, 36 and 36 mumol/kg, respectively: salicylic acid equivalent). Salicylic acid was detected in the blood following oral administration of salicyl-tyrosine and salicyl-methionine. In the case of salicyl-tyrosine, a relatively high blood concentration of salicylic acid was observed up to 36 h. Furthermore, the blood concentration of salicylic acid was sustained following rectal administration of salicyl-tyrosine and salicyl-methionine. A large difference in salicylic acid formation following oral administration was observed between salicyl-tyrosine and salicyl-methionine. Salicyl-tyrosine and salicyl-methionine were recovered from blood unchanged following intravenous administration, suggesting that presystemic de-conjugation was responsible for metabolism of the prodrugs following oral administration. Extensive salicylic acid formation in the cecum was found following intracecal administration of salicyl-tyrosine and salicyl-methionine. Also, in vitro incubation of salicyl-tyrosine and salicyl-methionine with gut contents showed that the primary location of hydrolysis was the hind gut. These results suggest that limited gastric and small intestinal absorbability of prodrug and metabolism by intestinal microorganisms were the major determinants of systemic bioavailability of parent drug.