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

Molecules

Nikolay Solovyev¹  Ekaterina Zubakina²  Marina Bezruchko²  Natalya Ivanenko²  Mikhail Maydin³  Galina Kireeva³  Ekaterina Gubareva³  Stepan Kruglov³  Elena Fedoros³ 

[1] Institute of Technology Sligo, Ash Lane, Sligo F91 YW50, Ireland;Institute of Toxicology, Federal Medical Biological Agency, 192019 Saint Petersburg, Russia;N.N. Petrov National Medical Research Center of Oncology, 197758 Saint Petersburg, Russia;

关键词: cis-diamminedichloridoplatinum (II);    hyperthermic intraperitoneal chemoperfusion;    Wistar rats;    platinum protein binding;    intravenous injection;    inductively coupled plasma mass spectrometry;   

DOI  :  10.3390/molecules25204733

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown