CISPLATIN METABOLITES IN PLASMA, A STUDY OF THEIR PHARMACOKINETICS AND IMPORTANCE IN THE NEPHROTOXIC AND ANTITUMOUR ACTIVITY OF CISPLATIN
CISPLATIN METABOLITES IN PLASMA, A STUDY OF THEIR PHARMACOKINETICS AND IMPORTANCE IN THE NEPHROTOXIC AND ANTITUMOUR ACTIVITY OF CISPLATIN
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DOI：
10.1016/0006-2952(84)90610-5
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发表时间：
1984-01-01
影响因子：
5.8
通讯作者：
MCBRIEN, DCH
中科院分区：
文献类型：
--
作者：
DALEYYATES, PT;MCBRIEN, DCH
对服用顺铂的大鼠，用高效液相色谱法研究含铂的超滤代谢产物在血浆中的出现率。在注射顺铂后15分钟内，除顺铂外，至少有7种药物还含有铂。15 mg/kg。顺铂在给药后3h内从血浆中几乎完全消除，但仍有代谢物存在。当顺铂与血浆体外孵育时，虽然比例不同，但形成相同的代谢物种类。在37℃孵育24小时后，产生含有不到4%顺铂的代谢物混合物。这种混合物，当注射到体内时。对大鼠来说，在铂的剂量下是肾毒性的，而顺铂在剂量上没有。当针对小鼠L1210白血病实验进行测试时，该代谢物混合物的抗肿瘤活性明显低于顺铂。虽然没有明确确定的代谢物种类，但证据表明，在主要的代谢物种类中，有顺铂的水解物和蛋氨酸替代产物。顺铂Met取代络合物的混合物既没有抗肿瘤作用，也没有肾毒性。当铂的剂量达到顺铂时，水解物就会产生肾毒性。这是第一次直接的实验证明，顺铂代谢产物的肾毒性比母体化合物更强，但抗肿瘤药物的效果不如母体化合物。
For rats dosed with cisplatin the rate of appearance in plasma of ultrafilterable metabolites containing Pt is investigated using HPLC [high-performance liquid chromatography]. At least 7 species containing platinum in addition to cisplatin are present in 15 min following injection i.p. of 15 mg/kg. Unchanged cisplatin was almost completely eliminated from the plasma within 3 h of dosing; however, metabolite species are still present. The same metabolite species form when cisplatin is incubated in vitro with plasma although in different proportions. After incubation for 24 h at 37.degree., a mixture of metabolites is produced which contains less than 4% cisplatin. This mixture, when injected i.p. into rats, is nephrotoxic at doses of Pt at which cisplatin is not. The mixture of metabolites has considerably less antitumor activity than cisplatin when tested against the mouse L1210 leukemia assay. Although no metabolite species was unequivocally identified, evidence suggests that among the principle metabolite species are a hydrolysis product and Met substitution products of cisplatin. A mixture of cisplatin Met substitution complexes showed neither antitumor nor nephrotoxic properties. A hydrolysis product is nephrotoxic at a dose of Pt at which cisplatin is not. This is the first direct experimental demonstration that cisplatin metabolites are more nephrotoxic, but less effective antitumor agents than the parent compound.