Goldman P
Johns Hopkins Med J. 1980 Jul;147(1):1-9.
Metronidazole is unique among therapies approved for trichomonas vaginitis and is useful also in the treatment of amebiasis, giardiasis and anaerobic bacterial infections. It has recently proved to be effective antibacterial prophylaxis for colon surgery. In spite of these important therapeutic properties the drug is considered risky for human use because of laboratory evidence that is it tumorigenic and mutagenic. A large excess risk of human cancer as the result of prior metronidazole exposure can probably be excluded on the basis of evidence already available. However, with the risk uncertain the drug should be restricted to patients who clearly will benefit from it and these patients should receive the drug in the minimal dose which is effective. Nitro group reduction is implicated in most of the biological properties of metronidazole including its mutagenicity. Two metabolites of the reduction of metronidazole, acetamide and N-(2-hydroxyethyl)-oxamic acid, form in the intestinal flora and can be found in the excreta of conventional rats but not of germfree rats. Thus the worrisome reaction implicated in the mutagenicity of metronidazole occurs in the flora. These metabolites produced by the flora complement those described in Ernest Bueding's laboratory. Bueding's group postulates metabolites which are mutagenic, and thus probably not yet reduced, whereas we postulate that our metabolites indicate that reduction, and thus possibly a mutagenic reaction, has already occurred. The metabolites we describe which are indicative of the reduction of metronidazole are also found in the urine of patients who take the drug. This has several possible implications which bear investigation. One is that a reactive intermediate may form in the flora and enter mammalian tissues. The other is that metronidazole is metabolized in the human to acetamide which is a carcinogen in its own right. Thus this drug,with its increasing number of useful clinical properties, continues to show laboratory properties which have uncertain implications for human risk.
甲硝唑在已获批用于治疗滴虫性阴道炎的疗法中独具特色，还可用于治疗阿米巴病、贾第虫病和厌氧菌感染。最近已证明它对结肠手术具有有效的抗菌预防作用。尽管具有这些重要的治疗特性，但由于实验室证据表明该药物具有致瘤性和致突变性，因此被认为对人类使用存在风险。根据现有证据，可能可以排除先前接触甲硝唑导致人类患癌风险大幅增加的情况。然而，由于风险尚不确定，该药物应仅限于显然会从中受益的患者，并且这些患者应接受有效最小剂量的药物治疗。硝基还原与甲硝唑的大多数生物学特性有关，包括其致突变性。甲硝唑还原产生的两种代谢产物，即乙酰胺和N-(2-羟乙基)草氨酸，在肠道菌群中形成，可在常规大鼠的排泄物中发现，但无菌大鼠的排泄物中则没有。因此，与甲硝唑致突变性有关的令人担忧的反应发生在菌群中。这些由菌群产生的代谢产物补充了欧内斯特·比丁实验室所描述的那些代谢产物。比丁的团队推测存在具有致突变性因而可能尚未还原的代谢产物，而我们推测我们所发现的代谢产物表明还原反应，进而可能的致突变反应已经发生。我们所描述的表明甲硝唑已发生还原的代谢产物也在服用该药物患者的尿液中被发现。这有几个可能值得研究的影响。一是可能在菌群中形成一种反应性中间体并进入哺乳动物组织。另一个是甲硝唑在人体内代谢为乙酰胺，而乙酰胺本身就是一种致癌物。因此，这种具有越来越多有用临床特性的药物，其实验室特性对人类风险的影响仍不确定。
