von Keutz E, Schlüter G
Institute of Toxicology, PH-Product Development, Bayer AG, Wuppertal, Germany.
Am J Cardiol. 1998 Aug 27;82(4B):11J-17J. doi: 10.1016/s0002-9149(98)00424-x.
Cerivastatin is a new but structurally distinct 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor ("statin"). It effectively decreases low-density lipoprotein (LDL) cholesterol at 1% of the doses of other currently available statins. The toxicology of cerivastatin was evaluated in a comprehensive program of studies including: (1) single- and multiple-dose toxicity studies in rats, mice, minipigs, dogs, and monkeys; (2) reproductive toxicity studies in rats and rabbits; (3) in vitro and in vivo mutagenicity assays in rats and mice; and (4) carcinogenicity studies in rats and mice. In addition, studies were undertaken to investigate the effects of cerivastatin on lens opacity, testicular tissue, and hemorrhage in dogs. Oral administration of single and multiple doses of cerivastatin over periods ranging from 4 weeks to 24 months was generally well tolerated. Adverse effects were similar to those observed with other statins and primarily involved the liver and muscle tissue. At the high doses used in the toxicologic studies, cerivastatin caused elevations in serum transaminases and creatine phosphokinase levels as well as some degeneration of muscle fibers in rats, mice, dogs, and minipigs. In dogs, the species most sensitive to statins, cerivastatin caused erosions and hemorrhages in the gastrointestinal tract, bleeding in the brain stem with fibroid degeneration of vessel walls in the choroid plexus, and lens opacity. Apart from minor morphologic changes in the testicular tissue of dogs--the only organ for which a comparably low margin of safety was observed--cerivastatin had no significant effects on the male or female reproductive system. Cerivastatin also caused no primary embryotoxic or teratogenic effects. With the exception of cerivastatin-induced effects on the eyes and testicles, administration of mevalonic acid reversed the toxicologic effects of cerivastatin, indicating that the toxic effects were related to its mode of action and not to any intrinsic toxicity of the molecule itself. There was no evidence that cerivastatin had any mutagenic effects and, in contrast to other statins, high doses of cerivastatin did not induce tumors in rats. The main metabolite of cerivastatin was well tolerated systemically in all animals, including dogs. Overall, cerivastatin has a similar toxicologic profile to other statins and is a well-tolerated HMG-CoA reductase inhibitor.
西立伐他汀是一种新型但结构独特的3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（“他汀类药物”）。它只需其他现有他汀类药物1%的剂量就能有效降低低密度脂蛋白（LDL）胆固醇。西立伐他汀的毒理学在一项全面的研究计划中进行了评估，包括：（1）在大鼠、小鼠、小型猪、狗和猴子身上进行的单剂量和多剂量毒性研究；（2）在大鼠和兔子身上进行的生殖毒性研究；（3）在大鼠和小鼠身上进行的体外和体内致突变性试验；以及（4）在大鼠和小鼠身上进行的致癌性研究。此外，还进行了研究以调查西立伐他汀对狗的晶状体混浊、睾丸组织和出血的影响。在4周至24个月的时间段内口服单剂量和多剂量的西立伐他汀，一般耐受性良好。不良反应与其他他汀类药物观察到的相似，主要涉及肝脏和肌肉组织。在毒理学研究中使用的高剂量下，西立伐他汀导致大鼠、小鼠、狗和小型猪的血清转氨酶和肌酸磷酸激酶水平升高，以及一些肌纤维变性。在对他汀类药物最敏感的狗身上，西立伐他汀导致胃肠道糜烂和出血、脑干出血以及脉络丛血管壁纤维样变性，还有晶状体混浊。除了狗的睾丸组织有轻微形态学变化外（狗是唯一观察到安全边际相对较低的器官），西立伐他汀对雄性或雌性生殖系统没有显著影响。西立伐他汀也没有引起原发性胚胎毒性或致畸作用。除了西立伐他汀对眼睛和睾丸的影响外，给予甲羟戊酸可逆转西立伐他汀的毒理学作用，这表明毒性作用与其作用方式有关，而不是与分子本身的任何内在毒性有关。没有证据表明西立伐他汀有任何致突变作用，并且与其他他汀类药物不同，高剂量的西立伐他汀在大鼠中不会诱发肿瘤。西立伐他汀的主要代谢产物在所有动物（包括狗）体内的全身耐受性良好。总体而言，西立伐他汀的毒理学特征与其他他汀类药物相似，是一种耐受性良好的HMG-CoA还原酶抑制剂。
