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Class: Antineoplastic agent.
Pharmacology: Pharmacodynamics: Mechanism of Action: Cisplatin is a platinum compound of which only the cis-isomer is active and has biochemical properties similar to those of bifunctional alkylating agents. It appears to produce intra- and inter-strand cross links which modify DNA structure and inhibit DNA synthesis. In addition, and to a lesser extent, cisplatin inhibits protein and RNA synthesis. It does not appear to be phase-specific in the cell cycle.
Clinical Trials: No data available.
Pharmacokinetics: Distribution: Cisplatin seems to concentrate in the liver, kidneys, small intestine and testes. It does not cross the blood brain barrier so does not penetrate the cerebrospinal fluid (CSF) to any great extent. CSF levels of cisplatin are low although significant amounts can be detected in intracerebral tumours. Animal studies show good uptake into ovarian and uterine tissue.
Elimination and Excretion: After IV injection, plasma decay is biphasic. The initial phase is rapid with a half-life of 25-49 minutes and this is followed by a prolonged elimination phase with a half-life of 2-4 days. This long elimination phase is probably due to a high degree of protein binding. Normally more than 90% is bound to plasma proteins, but this may be more during a slow infusion.
Excretion is predominantly renal. About 15-25% of a dose is rapidly excreted, mainly as intact drug, in the first 2-4 hours and 20-75% in the first 24 hours. The remainder represents drug bound to tissues or plasma proteins.
Toxicology: Preclinical safety data: Genotoxicity: Cisplatin has been shown to be genotoxic in vitro, in bacterial gene mutation assays, gene mutation assays in yeast (Saccharomyces cerevisiae D7) and mammalian cells (mouse lymphoma cells and Chinese hamster cells), in vitro chromosome aberration assays (in Chinese hamster cells and in human lymphocytes), in vitro DNA repair assays (Saccharomyces cerevisiae D7 and v79 Chinese hamster cells) and in vivo in a chromosome aberration assay in mouse bone marrow cells. Based on these studies, cisplatin is considered to present a genotoxic risk to humans.
Carcinogenicity: No formal carcinogenicity studies were performed. In a transplacental carcinogenicity study, a single IP injection of cisplatin (7.5 mg/kg) to pregnant mice on day 17 of gestation initiated and/or induced thymic lymphomas, lung tumours and proliferative kidney lesions in offsprings at week 25. In another transplacental carcinogenicity study, pregnant rats were given a single IP injection of cisplatin (5 mg/kg) on day 18 of gestation resulted in significantly higher incidences (20/82 in treatment vs 3/75 in control) of hepatocellular adenoma in offspring rats at 79 weeks. Therefore, cisplatin has a high carcinogenic potential in mice and rats.
