Effect of whole-body hyperthermia on lonidamine and doxorubicin pharmacokinetics and toxicity in dogs.
Six cycles of the maximum tolerable intravenous doses of lonidamine (400 mg/m2) and doxorubicin (30 mg/m2) were administered to three normothermic dogs and three dogs undergoing whole-body hyperthermia (WBH) (42 degrees C X 90 min), at 3-week intervals. Lonidamine pharmacokinetics was unaltered by WBH. WBH increased doxorubicin clearance 1.6-fold, however this trend was not statistically significant. WBH resulted in a 2.4-fold increase in the volume of distribution (Vdss) of doxorubicin 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 myelosuppression and cardiotoxicity were only minimally increased. Therefore, doxorubicin uptake in critical normal tissues was probably unaffected. The biochemical and haematologic toxicities observed 6 h and 1 week after each treatment did not appear to differ in character or severity from that reported in dogs receiving lonidamine +/- WBH or doxorubicin +/- WBH. These results suggest WBH did not decrease the maximum tolerable dose of doxorubicin when given with lonidamine, and that the antitumour activity of this combination should be assessed.
Price
G S
GS
Department of Companion Animal and Special Species Medicine, College of Veterinary Medicine, North Carolina State University, Raleigh 27606, USA.
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Riviere
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Cline
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Frazier
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Thrall
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D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D001647:Bile Acids and Salts / Q000097:blood; D001774:Blood Chemical Analysis; D004285:Dogs; D004317:Doxorubicin / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D006979:Hyperthermia, Induced; D007191:Indazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000648:ultrastructure; D008657:Metabolic Clearance Rate; D008854:Microscopy, Electron; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000648:ultrastructure; D014617:Vacuoles / Q000187:drug effects / Q000648:ultrastructure
D000970:Antineoplastic Agents; D001647:Bile Acids and Salts; D007191:Indazoles; D004317:Doxorubicin; C016371:lonidamine