Nonclinical toxicology studies with zidovudine: Genetic toxicity tests and carcinogenicity bioassays in mice and rats
Nonclinical toxicology studies with zidovudine: Genetic toxicity tests and carcinogenicity bioassays in mice and rats
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DOI：
10.1006/faat.1996.0118
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发表时间：
1996-08-01
期刊：
影响因子：
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通讯作者：
deMiranda, P
中科院分区：
文献类型：
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作者：
Ayers, KM;Clive, D;deMiranda, P
齐多夫定（ZDV），一种治疗中具有活性的抗病毒药物，仅在不存在代谢活化的情况下以最高试验浓度（4000至5000 μ g/ml）获得。在存在代谢活化的情况下，药物在1000 μ g/ml及更高浓度下具有弱致突变性。在不存在代谢活化的情况下处理24小时后，ZDV在浓度高达600 μ g/ml时具有中度致突变性;在下观察到剂量相关的结构染色体改变。在培养的人淋巴细胞中浓度为3 μ g/ml或更高。在0.3和1 μ g/ml的两个最低试验浓度下未观察到这种效应，而在0.5 μ g/ml和更高浓度下，BALB/c-3 T3细胞发生转化。在艾姆斯沙门氏菌平板掺入和预孵育修饰试验中（可能是由于低浓度ZDV的杀菌活性），浓度范围为0.01 - 10 μ g/平板或CD大鼠单次静脉内骨髓细胞遗传学试验中未观察到任何影响。在多次给药微核研究中，在100 - 1000 mg/kg/天剂量下，在小鼠中观察到微核红细胞增加，在500 mg/kg/天剂量下给药4或7天后，在大鼠和小鼠中观察到相似结果。在致癌性生物测定中，CD-1小鼠和CD大鼠分别接受20、30或40 mg/kg/天和80、220和300 mg/kg/天的调整剂量，小鼠给药长达22个月，大鼠给药长达24个月。ZDV在两个物种中均引起大红细胞正色素性贫血。在雄性小鼠或大鼠中未观察到致癌性证据。在雌性小鼠中，40 mg/kg/天剂量组动物发生了5例恶性和2例良性阴道上皮肿瘤。在30 mg/kg/天剂量组小鼠中观察到单个良性阴道上皮肿瘤。在大鼠中，在300 mg/kg/天剂量组动物中观察到两种恶性阴道上皮肿瘤。在小鼠中进行的7天研究中，显示ZDV没有雌激素活性。在口服药代动力学研究中，AUC为17和140 μ g/ml。hr，分别给予40或300 mg/kg ZDV的雌性小鼠和大鼠。相比之下，推荐日剂量下人体平均稳态浓度为0.62 μ g/ml。给予40或300 mg/kg ZDV的雌性小鼠和大鼠的24小时尿液浓度分别为1245和4417 μ g/ml。这些值比推荐日剂量下的人尿液浓度高约26倍和136倍。在大鼠和小鼠中静脉给予荧光素钠的一至三天研究中，证明了尿液逆行进入阴道。在随后的小鼠终生致癌性生物测定中，以5或20 mg ZDV/ml的生理盐水溶液浓度阴道内给予ZDV，在最高检测浓度下观察到13例阴道鳞状细胞癌。可以得出结论，经口致癌性研究中观察到的阴道肿瘤是阴道上皮长期局部暴露于高尿液浓度ZDV的结果。(C)1996年毒理学学会
Zidovudine (ZDV), an antiviral drug active in the treatment of obtained only at the highest concentrations tested (4000 to 5000 mu g/ml) in the absence of metabolic activation. In the presence of metabolic activation, the drug was weakly mutagenic at concentrations of 1000 mu g/ml and higher. Following 24 hr treatment in the absence of metabolic activation, ZDV was moderately mutagenic at concentrations up to 600 mu g/ml; dose-related structural chromosomal alterations were seen at. concentrations of 3 mu g/ml and higher in cultured human lymphocytes. Such effects were not noted at the two lowest concentrations tested, 0.3 and 1 mu g/ml, and BALB/c-3T3 cells were transformed at concentrations of 0.5 mu g/ml and higher. No effects were seen in the Ames Salmonella plate incorporation and preincubation modification assays (possibly due to bacteriocidal activity of ZDV at low concentrations) at concentrations ranging from 0.01 to 10 mu g/plate or in a single-dose intravenous bone marrow cytogenetic assay in CD rats. In multidose micronucleus studies, increases in micronucleated erythrocytes were seen in mice at doses of 100 to 1000 mg/kg/day, Similar results were seen in rats and mice after 4 or 7 clays of dosing at 500 mg/kg/day. In carcinogenicity bioassays, adjusted doses of 20, 30, or 40 mg/kg/day and 80, 220, and 300 mg/kg/day were given to CD-1 mice and CD rats, respectively, for up to 22 months in mice and 24 months in rats. ZDV caused a macrocytic, normochromic anemia in both species. No evidence of carcinogenicity was seen in male mice or rats. In female mice, five malignant and two benign vaginal epithelial neoplasms occurred in animals given 40 mg/kg/day. A single benign vaginal epithelial tumor was seen in a mouse given 30 mg/kg/day. In rats, two malignant vaginal epithelial neoplasms were seen in animals given 300 mg/kg/day. In a 7-day study in mice, ZDV was shown to be devoid of estrogenic activity. In an oral pharmacokinetics study, the. AUC was 17 and 140 mu g/ml . hr in female mice and rats given 40 or 300 mg/kg of ZDV, respectively. In contrast, the average steady-state concentration in humans at the recommended daily dose is 0.62 mu g/ml. Twenty-four hour urine concentrations were 1245 and 4417 mu g/ml in female mice and rats given 40 or 300 mg/kg of ZDV, respectively. These values were approximately 26- and 136-fold higher than the human urine concentration at the recommended daily dose. In a one- to three-day study with intravenously administered sodium fluoroscein in rats and mice, retrograde how of urine into the vagina was demonstrated, In a subsequent lifetime carcinogenicity bioassay in mice in which ZDV was given intravaginally at concentrations of 5 or 20 mg ZDV/ml in saline, 13 vaginal squamous cell carcinomas were seen at the highest concentration tested. It was concluded that the vaginal tumors seen in the oral carcinogenicity studies were the result of chronic local exposure of the vaginal epithelium to high urine concentrations of ZDV. (C) 1996 Society of Toxicology