EFFECT OF WHOLE-BODY HYPERTHERMIA ON LONIDAMINE AND DOXORUBICIN PHARMACOKINETICS AND TOXICITY IN DOGS

Six cycles of the maximum tolerable intravenous doses of lonidamine (4 00 mg/m(2)) and doxorubicin (30 mg/m(2)) were administered to three no rmothermic dogs and three dogs undergoing whole-body hyperthermia (WBH ) (42 degrees C X 90 min), at 3-week intervals. Lonidamine pharmacokin etics was unaltered by WBH. WBH increased doxorubicin clearance 1.6-fo ld, however this trend was not statistically significant. WBH resulted in a 2.4-fold increase in the volume of distribution (V-dss) of doxor ubicin relative to dogs treated under euthermic conditions (p < 0.001) . This finding suggests tissue extraction of doxorubicin was increased by WBH. The specific tissues in which this occurred is unknown, but m yelosuppression and cardiotoxicity were only minimally increased. Ther efore, doxorubicin uptake in critical normal tissues was probably unaf fected. The biochemical and haematologic toxicities observed 6 h and 1 week after each treatment did not appear to differ in character or se verity from that reported in dogs receiving lonidamine +/- WBH or doxo ntbicin +/- WBH. These results suggest WBH did not decrease the maximu m tolerable dose of doxorubicin when given with lonidamine, and that t he antitumour activity of this combination should be assessed.