Nelson S D, Forte A J, McMurtry R J
Res Commun Chem Pathol Pharmacol. 1978 Oct;22(1):61-71.
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.
制备了对羟基乙酰苯胺（对乙酰氨基酚）和对乙氧基乙酰苯胺（非那西丁）的N-甲基类似物，并对其毒性进行了测试。发现N-甲基对乙酰氨基酚在给予对乙酰氨基酚时会在相同动物中引起大量肝坏死的剂量下，对小鼠、大鼠或仓鼠均未引起肝坏死。在这些剂量水平下，对乙酰氨基酚及其N-甲基化类似物均未引起高铁血红蛋白血症。给予大剂量对乙酰氨基酚（900mg/kg皮下注射）的Fischer大鼠近端肾小管出现坏死，而N-甲基对乙酰氨基酚在更高剂量水平（1800mg/kg皮下注射）下未引起肾损伤。N-甲基非那西丁在剂量高于非那西丁引起肝坏死的剂量时，对经3-甲基胆蒽（3-MC）预处理的仓鼠未引起明显的肝坏死。此外，与非那西丁不同，N-甲基非那西丁在小鼠、大鼠或仓鼠中未引起广泛的高铁血红蛋白血症。
