van der Vijgh W J
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Clin Pharmacokinet. 1991 Oct;21(4):242-61. doi: 10.2165/00003088-199121040-00002.
Carboplatin [diammine(1,1-cyclobutanedicarboxylato)platinum(II)] is one of the most promising second generation platinum compounds. Its greater chemical stability in comparison with cisplatin accounts for its lower reactivity with nucleophilic sites of DNA, and may therefore be related to the higher dose necessary to obtain an antitumour effect similar to that of cisplatin. The lower reactivity with proteins may be related to the observed reduction in nephrotoxicity. Its dose-limiting toxicity is myelosuppression, especially thrombocytopenia. Total and ultrafilterable platinum are detected by flameless atomic absorption spectrophotometry, and high performance liquid chromatography with either UV or electrochemical detection is used for the quantification of carboplatin. These 3 species have been measured as a function of time in biological fluids and tissues to determine their pharmacokinetics. Carboplatin has high stability in infusion fluids in the absence of chloride, but it is less stable in plasma and urine. Protein binding is limited, while the low uptake in red blood cells appears to be species dependent. Commonly, carboplatin is administered intravenously, and its pharmacokinetics are linear up to a dose of 2400 mg/m2. In comparison with cisplatin, carboplatin has longer half-lives of ultrafilterable platinum (23 and 120 min versus 6 and 36 min for distribution and initial elimination half-lives, respectively) and a higher cumulative urinary platinum excretion (77 versus 28% of the dose in 24 h), both due to the lower protein binding of carboplatin. The terminal half-life of total platinum is comparable between the 2 compounds (5.8 versus 5.4 days). This value most probably represents the breakdown of proteins to which both compounds are irreversibly bound. Relationships between pharmacokinetics (area under the curve) and pharmacodynamics (extent of myelosuppression or extent of existing kidney failure) have allowed the development of equations for rational dosage reduction. Intraperitoneal administration has been used in cases of residual ovarian cancer: as a result of its higher hydrophilicity and higher molecular weight, carboplatin is cleared more slowly from the peritoneal cavity than cisplatin (6 vs 15 ml/min). The low bioavailability (4 to 12%) and the gastrointestinal side effects observed did not warrant further studies with oral administration. In contrast to results from animal studies, the modulation of carboplatin-induced myelosuppression by diethyldithiocarbamate (DDTC) was not clinically successful. Valuable alternatives may be the combination with WR2721 or colony-stimulating factors.
卡铂[二氨（1,1 - 环丁烷二羧酸根）铂（II）]是最有前景的第二代铂类化合物之一。与顺铂相比，其化学稳定性更高，这导致它与DNA亲核位点的反应性较低，因此可能与获得与顺铂相似的抗肿瘤效果所需的更高剂量有关。与蛋白质的反应性较低可能与观察到的肾毒性降低有关。其剂量限制性毒性是骨髓抑制，尤其是血小板减少。通过无火焰原子吸收分光光度法检测总铂和可超滤铂，使用紫外或电化学检测的高效液相色谱法定量卡铂。已测定这三种物质在生物体液和组织中的含量随时间的变化，以确定它们的药代动力学。在没有氯离子的情况下，卡铂在输液中具有高稳定性，但在血浆和尿液中稳定性较差。蛋白质结合有限，而在红细胞中的低摄取似乎因物种而异。通常，卡铂通过静脉给药，其药代动力学在剂量高达2400mg/m²时呈线性。与顺铂相比，卡铂的可超滤铂半衰期更长（分布半衰期和初始消除半衰期分别为23分钟和120分钟，而顺铂为6分钟和36分钟），累积尿铂排泄更高（24小时内分别为剂量的77%和28%），这两者都是由于卡铂的蛋白质结合较低。两种化合物的总铂终末半衰期相当（分别为5.8天和5.4天）。这个值很可能代表了两种化合物不可逆结合的蛋白质的分解。药代动力学（曲线下面积）和药效学（骨髓抑制程度或现有肾衰竭程度）之间的关系使得能够开发合理剂量减少的方程。对于残留卵巢癌病例，已采用腹腔内给药：由于其亲水性更高和分子量更大，卡铂从腹腔清除的速度比顺铂慢（分别为6ml/min和15ml/min）。观察到的低生物利用度（4%至12%）和胃肠道副作用不支持进一步进行口服给药研究。与动物研究结果相反，二乙基二硫代氨基甲酸盐（DDTC）对卡铂诱导的骨髓抑制的调节在临床上并不成功。有价值的替代方法可能是与WR2721或集落刺激因子联合使用。
