Formation of a thiomethyl metabolite of phenacetin and acetaminophen in dogs and man

Conjugates of 3-methylthio-4-hydroxyactanilide were found in the urine of dogs and humans treated with phenacetin (4-ethoxyacetanilide) or acetaminophen (4-hydroxyacetanilide). About 1% to 3% of the administered dose was excreted as this thiomethyl metabolite after administration of phenacetin or acetaminophen to dogs. An average of 0.39% of the dose was excreted in the urine as 3-methylthio-4-hydroxyacetanilide conjugates after administration of phenacetin to several subjects, and an average of 0.66% of the dose was excreted as this metabolite in the urine after administration of acetaminophen to humans. The possibility that the thiomethyl metabolite is derived from a mercapturic acid conjugate or an N-hydroxy derivative of phenacetin or acetaminophen is discussed.