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The first-pass metabolism of ethenzamide (ETB), which is considered to be a pro-drug of salicylamide (SAM), was studied in rats in order to compare with that of SAM. The extent of first-pass metabolism after oral ETB estimated by oral and intravenous administration was as much as 82% and remaining 18% ETB entered into systemic circulation. Further, it has been confirmed that the first-pass metabolism of ETB is not due to the intestine but entirely due to the liver in which de-ethylation to SAM occurred at first, followed by exclusive conjugation with sulfuric acid and little SAM enters into systemic circulation. On the other hand, it was previously demonstrated in rats that per se administered SAM is subjected to first-pass metabolism both in the gut and liver as much as about 60% and the remaining 40% entered the systemic circulation. Thus, the behavior of SAM is considerably different depending upon whether it is per se administered or formed from ETB through metabolism. The fact that little SAM appears in the systemic circulation after oral administration of ETB suggests that the pharmacological activity of ETB comes from its own attributes but not from SAM.

Comparison of the first-pass metabolism of ethenzamide and salicylamide in rats.