PRECLINICAL PHARMACOLOGICAL EVALUATION OF GELDANAMYCIN AS AN ANTITUMOR AGENT
PRECLINICAL PHARMACOLOGICAL EVALUATION OF GELDANAMYCIN AS AN ANTITUMOR AGENT
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DOI：
10.1007/bf00689048
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发表时间：
1995-08-01
影响因子：
3
通讯作者：
MALSPEIS, L
中科院分区：
文献类型：
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作者：
SUPKO, JG;HICKMAN, RL;MALSPEIS, L
抗肿瘤抗生素格尔达霉素（GM; NSC 122750）是一种天然存在的苯醌类ansamycin，其血浆药代动力学在小鼠和比格犬中进行了表征。通过静脉注射治疗的小鼠和狗的血浆中获得了远高于0.1 μ g/ml的转基因浓度，这通常对体外对药物有反应的肿瘤细胞系有效。然而，药物的全身持续时间相对较短。在给予最大耐受剂量后3-4小时内，血浆水平降至0.1 μ g/ml以下，小鼠约为20 mg/kg，狗约为4 mg/kg。该药物在所研究的剂量范围内表现出线性药代动力学行为。然而，其倾向在种间存在显著差异。虽然GM在小鼠体内的平均生物半衰期（77.7 min）略长于狗体内（57.9 min），但其在狗体内的平均停留时间（46.6 min）比在小鼠体内（20.7 min）长两倍多。然而，狗从血浆中清除药物的速度（49.4 ml/min / kg）比小鼠（30.5 ml/min / kg）快得多。这些明显的异常主要与总体药物处置终末期相对重要性的差异有关。肝脏似乎是狗急性药物毒性的主要靶器官。2.0和4.2 mg/kg剂量均使血清转氨酶水平和其他急性肝坏死特征肝功能指标升高。其他影响包括轻微胃肠道毒性症状和与较轻肾毒性一致的血清化学参数改变。药物相关的毒性似乎是可逆的。考虑到GM以及基于结构相似的其他苯醌类ansamycin可能产生急性肝毒性反应，需要额外的药理学和治疗信息来确定这些化合物是否可用于临床开发。
The plasma pharmacokinetics of the antitumor antibiotic geldanamycin (GM; NSC 122750), a naturally occurring benzoquinoid ansamycin, was characterized in mice and a beagle dog. Concentrations of GM well above 0.1 mu g/ml, which was typically effective against neoplastic cell lines responsive to the drug in vitro, were achieved in the plasma of the mice and the dog treated by i.v. injection. However, the systemic duration of the drug was relatively short. Plasma levels decayed below 0.1 mu g/ml within 3-4 h after administration of the apparent maximum tolerated doses, which were approximately 20 mg/kg for the mice and 4 mg/kg for the dog. The drug exhibited linear pharmacokinetic behavior within the dose ranges studied. However, there were significant interspecies differences in its disposition. Whereas the mean biological half-life of GM was slightly longer in the mice (77.7 min) than in the dog (57.9 min), its mean residence time in the dog (46.6 min) was more than twofold greater than that observed in the mice (20.7 min). Nevertheless, the drug was cleared from plasma much faster by the dog (49.4 ml/min per kg) than by the mice (30.5 ml/min per kg). These apparent anomalies were principally associated with differences in the relative significance of the terminal phase upon overall drug disposition. The liver appeared to be the principal target organ of acute drug toxicity in the dog. Doses of 2.0 and 4.2 mg/kg both produced elevations in serum levels of the transaminases and other indicators of liver function characteristic of acute hepatic necrosis. Additional effects included symptoms of minor gastrointestinal toxicity and alterations in serum chemistry parameters consistent with less severe nephrotoxicity. Drug-related toxicity appeared to be reversible. In consideration of the potential for acute hepatotoxic reactions to GM, as well as to the other benzoquinoid ansamycins based upon structural analogy, additional pharmacological and therapeutic information is required to ascertain whether these compounds are viable candidates for clinical development.