Decreased toxicity of the N-methyl analogs of acetaminophen and phenacetin.

The N-methyl analogs of p-hydroxyacetanilide (acetaminophen) and p-ethoxyacetanilide (phenacetin) were prepared and tested for toxicity. N-Methylacetaminophen was found to cause no hepatic necrosis in mice, rats, or hamsters in doses that caused massive hepatic necrosis in the same animals when acetaminophen was administered. Neither acetaminophen nor its N-methylated analog caused methemoglobinemia at these dose levels. Fischer rats that were administered large doses of acetaminophen (900 mg/kg s.c.) sustained necrosis in the proximal renal tubules, whereas N-methylacetaminophen caused no renal injury at higher dose levels (1800 mg/kg s.c.). N-Methylphenacetin caused no observable hepatic necrosis in 3-methylcholanthrene (3-MC) pretreated hamsters at dose levels higher than those in which phenacetin caused hepatic necrosis. Also, in contrast to phenacetin, N-methylphenacetin did not cause extensive methemoglobinemia in mice, rats, or hamsters.