Robison R L, Suter W, Cox R H
Department of Drug Safety, Sandoz Research Institute, East Hanover, New Jersey 07936.
Fundam Appl Toxicol. 1994 Jul;23(1):9-20. doi: 10.1006/faat.1994.1073.
The HMG-CoA reductase inhibitors are a new and novel class of cholesterol-lowering agents which are widely used worldwide. Fluvastatin is the first entirely synthetic compound in this class and is structurally distinct from fungal metabolite derivatives which are already marketed. As the liver is the site of some toxic effects for these compounds, it was not entirely unexpected that liver cancer was found in rats and/or mice with the first three marketed compounds, lovastatin, pravastatin, and simvastatin. Four lifetime carcinogenicity studies (two rat and two mouse) did not give any evidence that fluvastatin induced liver tumors in rodents. Fluvastatin induced thyroid neoplasms in rats and forestomach papillomas in rodents, as other compounds in this pharmacologic class have also done. The genotoxic potential of fluvastatin has been assessed in vitro using Salmonella typhimurium, Escherichia coli (gene mutations), V79 Chinese hamster cells (HGPRT gene mutations, chromosomal aberrations), rat hepatocyte primary cultures (DNA repair), and BALB/3T3 cells (malignant transformations). Fluvastatin was also tested in vivo for clastogenicity using the mouse bone marrow micronucleus test and by performing a cytogenetic analysis in the rat bone marrow after acute and subacute treatment. In all seven assays fluvastatin was found to be free of any genotoxic potential.
HMG - CoA还原酶抑制剂是一类新型的降胆固醇药物，在全球范围内广泛使用。氟伐他汀是该类药物中首个完全合成的化合物，在结构上与已上市的真菌代谢产物衍生物不同。由于肝脏是这些化合物产生某些毒性作用的部位，因此在使用前三种上市化合物洛伐他汀、普伐他汀和辛伐他汀的大鼠和/或小鼠中发现肝癌并不完全出乎意料。四项终生致癌性研究（两项大鼠研究和两项小鼠研究）未提供任何证据表明氟伐他汀会在啮齿动物中诱发肝肿瘤。与该药理类别的其他化合物一样，氟伐他汀在大鼠中诱发了甲状腺肿瘤，在啮齿动物中诱发了前胃乳头瘤。已使用鼠伤寒沙门氏菌、大肠杆菌（基因突变）、V79中国仓鼠细胞（次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶基因突变、染色体畸变）、大鼠肝细胞原代培养物（DNA修复）和BALB / 3T3细胞（恶性转化）在体外评估了氟伐他汀的遗传毒性潜力。还使用小鼠骨髓微核试验并在急性和亚急性处理后的大鼠骨髓中进行细胞遗传学分析，在体内测试了氟伐他汀的致断裂性。在所有这七种试验中，均发现氟伐他汀没有任何遗传毒性潜力。
