P26-6 Pharmacokinetic advantage of HIPEC with cisplatin over systemic administration of cisplatin

Abstract

Background: Hyperthermic intraperitoneal chemoperfusion (HIPEC) is thought to have less side effects than intravenous (i.v.) chemotherapy due to lower systemic absorption of drugs. The underlying mechanisms of this difference in toxicity remain unknown. We studied absorption and distribution of cisplatin after HIPEC and i.v. injection in a rat model. Methods: Female Wistar rats (N¼9) received either HIPEC with cisplatin, 20 mg/kg (N¼9), or cisplatin i.v., once, 4 mg/kg (N¼9). These were maximum tolerated doses. Six animals from each group were used for blood sampling at following time points: prior to administration, in 15,20,30,45,60,70 minutes, in 8,12 hours, and in 1,2,5 days after administration, with following euthanasia. Three animals from each group were euthanised in 24 hours after cisplatin administration. Samples of ovaries, liver and kidneys were used to study cisplatin content and level of platinum free of blood plasma proteins.Results: Cisplatin content in blood plasma at different time points as well as secretion kinetics didn't differ significantly between groups. Cisplatin content in kidneys of rats after i.v. administration went up from 5.9AE1.1 to 11.2AE1.4 mg/kg, and for HIPEC it changed from 1.2AE0.3 to 1.9AE0.3 mg/kg (p<0.001). IHC with gamma H2AX (DNA damage marker) also showed larger damage to kidneys after i.v. administration. Fraction of free platinum in blood filtrate samples after HIPEC (taken right after HIPEC, point of peak concentration) was 0.51AE0.02 versus 0.67AE0.02 after i.v. injection (taken in 15 min after injection, point of peak concentration) (p¼0.0014). Conclusion:Lower toxicity of HIPEC is due to lower content of free platinum in blood plasma rather than lower overall concentration of cisplatin in the blood as it was thought previously. Financial support by RSF grant 18-75-100-17.