The safety evaluation of fluvastatin, an HMG-CoA reductase inhibitor, in beagle dogs and rhesus monkeys
The safety evaluation of fluvastatin, an HMG-CoA reductase inhibitor, in beagle dogs and rhesus monkeys
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DOI：
10.1006/faat.1996.0005
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发表时间：
1996-01-01
期刊：
影响因子：
--
通讯作者：
Tse, FLS
中科院分区：
文献类型：
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作者：
Hartman, HA;Myers, LA;Tse, FLS
氟伐他汀是β-羟基-β-甲基-戊二酰-辅酶A（HMG-CoA）还原酶（肝胆固醇合成生物合成途径中的限速酶）的强效合成竞争性抑制剂。治疗适应症是降低升高的总胆固醇和低密度脂蛋白胆固醇水平。报告了在比格犬中进行的4项毒性研究和在恒河猴中进行的1项氟伐他汀经口给药研究的结果。在两项为期26周的犬研究中，剂量为0、1、8或48 mg/kg/天（第7周降至36 mg/kg/天）和0、6、24或36 mg/kg/天（第2周降至30 mg/kg/天）。在一项为期2年的犬研究中，剂量为0、1、8或16 mg/kg/天。26周猴研究中的剂量水平为0、0.6、12和48 mg/kg/天（第17周增至84 mg/kg/天，第22周增至108 mg/kg/天）。在这些研究中，评价包括临床和体格检查、体重和摄食量、心电图、检眼镜检查、血液学和临床化学、尿分析、血药浓度以及观察到的病变和代表性组织的肉眼和显微镜检查。在26周和52周犬研究和猴研究中，研究了晶状体生物化学、肝微粒体的HMG-CoA还原酶活性和血清脂质浓度。第四项犬研究是一项单次给药毒代动力学研究，其中监测48 mg/kg [H-3]-氟伐他汀长达2周。取样仅限于眼组织用于酶分析。大于或等于24 mg/kg/天的剂量在犬中具有致死性。在致死剂量下，观察到共济失调、惊厥、便血、多灶性充血和出血、延髓孤立软化灶和肝坏死。在≥ 8 mg/kg/天剂量下发生体重增加减少、呕吐、白内障、肝酶升高、胆固醇降低和胆囊炎症伴粘膜增生。与其他HMG-CoA还原酶抑制剂相比，氟伐他汀未引起犬的显著中枢神经系统出血或睾丸变化。猴对氟伐他汀暴露耐受良好，仅观察到轻度胆囊变化。在12和48/84/108 mg/kg/天剂量组中出现血清胆固醇降低和胆囊粘膜轻度增生。(C)1996年毒理学学会
Fluvastatin is a potent synthetic competitive inhibitor of beta-hydroxy-beta-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the biosynthetic pathway for hepatic cholesterol synthesis. The therapeutic indication is reduction of elevated total and low-density lipoprotein cholesterol levels. Results from four toxicity studies in beagle dogs and one study in rhesus monkeys following oral administration of fluvastatin are reported. In two 26-week dog studies, doses were 0, 1, 8, or 48 mg/kg/day (reduced to 36 mg/kg/day in Week 7) and 0, 6, 24, or 36 mg/kg/day (reduced to 30 mg/kg/day in Week 2). In a 2-year dog study, doses were 0, 1, 8, or 16 mg/kg/day. Dose levels in the 26-week monkey study were 0, 0.6, 12, and 48 mg/kg/day (raised to 84 mg/kg/day in Week 17 and to 108 mg/kg/day in Week 22). In these studies, evaluations included clinical and physical examinations, body weight and food consumption, electrocardiography, ophthalmoscopy, hematology and clinical chemistries, urinalysis, blood drug concentration, and macroscopic and microscopic examinations of observed lesions and representative tissues. In the 26- and 52-week dog studies and the monkey study, lenticular biochemistry, the HMG-CoA reductase activity of liver microsomes, and serum lipid concentrations were investigated. The fourth dog study was a single-dose toxicokinetic study in which 48 mg/kg [H-3]-fluvastatin was monitored for up to 2 weeks. Sampling was limited to ocular tissues for enzyme analysis. Doses of greater than or equal to 24 mg/kg/day were lethal in dogs. At lethal doses, ataxia, convulsions, fecal blood, multifocal congestion and hemorrhage, isolated foci of malacia in the medulla oblongata, and liver necrosis were observed. Reduced weight gain, emesis, cataracts, elevated liver enzymes, reduced cholesterol, and gallbladder inflammation with mucosal hyperplasia occurred at greater than or equal to 8 mg/kg/day. In contrast to other HMG-CoA reductase inhibitors, fluvastatin did not cause significant central nervous system hemorrhage or testicular changes in dogs. Monkeys tolerated exposure to fluvastatin well with only mild gallbladder changes observed. Reduced serum cholesterol and slight hyperplasia of the gallbladder mucosa occurred in the 12 and 48/84/108 mg/kg/day groups. (C) 1996 Society of Toxicology