Abstract
Hyperthermic intraperitoneal chemoperfusion (HIPEC) is an established form of locoregional chemotherapy of peritoneum tumors. However, its efficacy and safety status remain a controversy, partially, due to scarce data on pharmacokinetics and toxicity profile of drugs under HIPEC. In the current study, 24 female Wistar rats were randomly assigned to receive cisplatin as HIPEC (n = 12, 20 mg/kg) or intravenously (i.v., n = 9, 4 mg/kg). The subgroups of three animals were used for the initial, intermediate, and late phases of the pharmacokinetic assessment. The animals were sacrificed on days 1 and 5. Blood, liver, kidney, and ovaries were evaluated for platinum content. Histological and immunohistochemical evaluation was undertaken in the liver and kidney. A trend for higher blood plasma platinum levels was observed for HIPEC compared to i.v. Significantly lower (p < 0.001) relative platinum binding to the proteins was observed in HIPEC animals compared to the i.v. administration. A five-fold higher concentration of cisplatin in HIPEC resulted in a ca. 2.5-fold increase in total blood platinum and ca. two-fold increase in blood ultrafitrable platinum (“free” Pt). Immunohistochemistry revealed higher kidney and liver damage after i.v. administration of cisplatin compared to HIPEC, although a five-fold higher dose of cisplatin was applied in HIPEC. Together with relatively lower absorption to the systemic circulation in HIPEC, higher protein binding is probably the primary reason for lower observed toxicity in HIPEC animals.
Highlights
Platinum (Pt)-based drugs are a g group of cytotoxic agents with DNA binding capacities [1], suppressing the replication [2]
Cisplatin, when administered as Hyperthermic intraperitoneal chemoperfusion (HIPEC), has a more favorable toxicity profile compared to Cisplatin, when administered as HIPEC, has a more favorable toxicity profile compared to systemic administration, which has been one of the rationales to perform HIPEC instead of i.v
Drugs compared to the systemic route is among the arguments in favor of HIPEC [24,27,28]
Summary
Platinum (Pt)-based drugs are a g group of cytotoxic agents with DNA binding capacities [1], suppressing the replication [2]. These properties of platinum complexes were first described in the late 1960s with the discovery of the cytostatic properties of cisplatin, cis-dichlorodiammineplatinum (II) [3]. The development of other platinum-based drugs, first of all, that of carboplatin and oxaliplatin, was stimulated by the side effects of cisplatin, including nephrotoxicity, ototoxicity, and peripheral nervous system disorders [7,8,9]. The main shortcomings of platinum-based cytostatic agents are associated with their insufficient selectivity for malignant cells, severe side effects, and drug resistance for some tumor-types [10,11]
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