HYPERTHERMIC INTRAPERITONEAL DOXORUBICIN - PHARMACOKINETICS, METABOLISM, AND TISSUE DISTRIBUTION IN A RAT MODEL

Background: The cytotoxic effect of several anticancer agents, includi ng doxorubicin, can be enhanced by hyperthermia. The purpose of this s tudy was to evaluate the effect of hyperthermia on the pharmacokinetic s, metabolism, and tissue distribution of intraperitoneal (i.p.) doxor ubicin in a rodent model. Methods: Doxorubicin was given i.p. to 20 Sp rague-Dawley rats at a dose of 2 mg/kg over 60 min. Rats were randomiz ed into two groups according to the temperature of the peritoneal perf usate: group NT received normothermic (37 degrees C) i.p. doxorubicin; group HT received hyperthermic (43 degrees C) i.p. doxorubicin. Durin g the course of i.p. chemotherapy, peritoneal fluid and blood were sam pled every 10 min. At the end of the procedure, rats were sacrificed a nd tissue samples (liver, spleen, small bowel, omentum, bladder, diaph ragm, abdominal wall, heart) were collected. Concentrations of doxorub icin and its aglycone metabolites were determined in peritoneal fluid, plasma, and tissues by HPLC. Results: No significant differences in a reas under the curve (AUC) of peritoneal fluid doxorubicin and plasma doxorubicin were found between group NT and group HT. AUC ratios (AUC peritoneal fluid/AUC blood) were 87.9 for group NT and 82.9 for group HT. Group HT exhibited increased doxorubicin concentrations for all in traabdominal tissues. These differences were significant for spleen (P = 0.03), small bowel (P = 0.03), and omentum (P = 0.03). Doxorubicin aglycone was detected in plasma of both groups within the first 10 min of the procedure. There was a significant (P < 0.001) increase in pla sma aglycone AUC for group HT when compared with group NT. Group HT ex hibited increased aglycone concentration for all tissues. This differe nce was significant for liver (P < 0.001) and bladder (P < 0.001). Con clusion: Hyperthermia did not affect significantly the pharmacokinetic s of i.p. doxorubicin. Tissue concentrations of doxorubicin in small b owel, omentum, and spleen were significantly increased when the drug w as administered by hyperthermic i.p. perfusion. Hyperthermia increased significantly the doxorubicin aglycone concentrations in plasma, live r, and bladder.