Modeling of Chemoperfusion vs. Intravenous Administration of Cisplatin in Wistar Rats: Adsorption and Tissue Distribution

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.

Efficacy and Safety of Systemic and Locoregional Cisplatin Chronotherapy in Rats with Ovarian Carcinoma

“…Higher drug doses may be used compared to systemic administration. 25 In this study, morning cisplatin treatment appeared to be more effective and less toxic than evening treatment. These results correspond well to those described by Seto et al, where peripheral neuropathy was less aggravated in morning-treated rats.…”

“…The advantages of HIPEC over systemic drug administration have been confirmed in previous experimental studies. 25 , 39 …”

“…Cisplatin was administered on day 5 after ovarian cancer transplantation either intravenously or as HIPEC at 4 or 20 mg/kg correspondingly, which were the maximum tolerated doses. 25 The HIPEC protocol has been described elsewhere. 24 …”

“…The advantages of HIPEC over systemic drug administration have been confirmed in previous experimental studies. 25,39 This is mainly explained by the fact that cisplatin administered intraperitoneally affects tumor cells directly, while the absorbed portion of the drug binds with proteins, which leads to lower toxicity. Higher drug doses may be used compared to systemic administration.…”

Protein Binding of a Novel Platinum-Based Anticancer Agent BP-C1 Containing a Lignin-Derived Polymeric Ligand

“…Our recent study [23] demonstrated that increased protein binding might be crucial for the reduced side effects of cisplatin under hyperthermic intraperitoneal chemoperfusion compared to the standard infusion administration. The aim of the current study was to study the protein binding of a novel anticancer agent with the polymeric lignin-derived ligand BP-C1 using equilibrium dialysis.…”