DECREASED TOXICITY OF N-METHYL ANALOGS OF ACETAMINOPHEN AND PHENACETIN

Abstract

The N-methyl analogs of p-hydroxyacetanilide (acetaminophen) and p-ethoxyacetanilide (phenacetin) were prepared and tested for toxicity. N-methylacetaminophen caused 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 pretreated hamsters at dose levels higher than those in which phenacetin caused hepatic necrosis. In contrast to phenacetin, N-methylphenacetin did not cause extensive methemoglobinemia in mice, rats or hamsters.