The effects of localized hyperthermia on blood flow and cisplatin pharmacokinetics

This study was undertaken to gain knowledge of the effects of localized hyperthermia (43°C, 1 hr) on blood perfusion rates as well as cisplatin pharmacokinetics in Sprague-Dawley rats with induced mammary adenocarcinomas.

Rats were administered either cisplatin alone, local hyperthermia alone (43°C for 1 hr), cisplatin plus hyperthermia, or neither. Blood flows in tumor and normal tissues were measured at different times relative to hyperthermia. Cisplatin was administered to another group of rats at times corresponding to those in the hyperthermia only group. Drug concentrations were determined in tumors and plasma.

Overall, treatment means of pharmacokinetic parameters (distribution and elimination half-lives, area under the plasma concentration versus time curve, clearance, A and B intercepts, α and β rate constants) were not significantly different (ANOVA). However when pairwise comparisons were made, there were significant differences in several pharmacokinetic parameters.

The distribution half-life of the drug only group was significantly shorter (p<0.05) than the group receiving drug one hour before, at the beginning of, and one hour after a hyperthermia treatment. The average distribution half-life of rats receiving drug 1 hour before heat was significantly longer (p < 0.05) than groups receiving drug only, drug at the beginning of hyperthermia, or drug a hour after hyperthermia. The elimination half-life of the group receiving drug 1 hr before heat was significantly longer (p < 0.05) than all other groups. Clearance was significantly greater (p < 0.05) when drug was administered at the end of heat than when it was given 1 hr after hyperthermia.

The volume of distribution of the central compartment of the group given drug at the end of hyperthermia was significantly greater (p < 0.05) than the group which received drug 1 hour after hyperthermia. The steady state volume of distribution was significantly greater (p < 0.05) when drug was given 1 hour before hyperthermia than when drug was given at the beginning of heat, end of heat, or 1 hour after heat.

The average tumor concentration of the group of rats receiving drug at the beginning of heat was significantly greater (p < 0.05) than the average for the group in which rats where given drug at the end of a hyperthermia treatment. A Pearson correlation analysis revealed that tumor drug concentration was directly correlated to the area under the curve and the A intercept and indirectly half-life of rats receiving drug 1 hour before heat was significantly longer (p < 0.05) than groups receiving drug only, drug at the beginning of hyperthermia, or drug a hour after hyperthermia. The elimination half-life of the group receiving drug 1 hr before heat was significantly longer (p < 0.05) than all other groups. Clearance was significantly greater (p < 0.05) when drug was administered at the end of heat than when it was given 1 hr after hyperthermia. The volume of distribution of the central compartment of the group given drug at the end of hyperthermia was significantly greater (p < 0.05) than the group which received drug 1 hour after hyperthermia. The steady state volume of distribution was significantly greater (p < 0.05) when drug was given 1 hour before hyperthermia than when drug was given at the beginning of heat, end of heat, or 1 hour after heat. The average tumor concentration of the group of rats receiving drug at the beginning of heat was significantly greater (p < 0.05) than the average for the group in which rats where given drug at the end of a hyperthermia treatment. A Pearson correlation analysis revealed that tumor drug concentration was directly correlated to the area under the curve and the A intercept and indirectly correlated to the rate of clearance and volume of distribution of the central compartment.

Similarly, blood flow did not differ significantly; however, the data reveals a trend. Blood flow was highest immediately after a hyperthermia treatment and slowed over a three hour period to reach an approximate untreated value at three hours post treatment.