Effect of whole-body hyperthermia on the pharmacokinetics and toxicity of lonidamine in dogs.
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| Abstract |
The pharmacokinetics and toxicity of intravenous lonidamine were investigated in dogs receiving four cycles of lonidamine (400 or 800 mg/m2) +/- whole-body hyperthermia (WBH). Clearance and volume of distribution in dogs receiving lonidamine during WBH increased 1.6-2.3 and 1.9-3.5-fold respectively, relative to dogs receiving lonidamine under euthermic conditions (p < 0.02). In dogs receiving lonidamine under euthermic conditions or 400 mg/m2 + WBH, the area under the lonidamine concentration versus time curve (AUC) measured during the fourth treatment was 21-58% lower than the first treatment AUC. However, in dogs receiving 800 mg/m2 + WBH, the fourth treatment AUC was four-fold higher than the first treatment AUC (p < 0.02). This suggests repeated exposure to 800 mg/m2 lonidamine and WBH impairs lonidamine metabolism. Weakness, hypoglycaemia, and elevations in amylase, alanine aminotransferase, alkaline phosphatase and bilirubin were more severe or occurred exclusively in dogs receiving 800 mg/m2 + WBH. Since these changes were attributable to marked AUC increases, which occurred secondary to repeated exposure to 800 mg/m2 lonidamine during WBH, 400 mg/m2 was identified as the maximum tolerable dose to be administered intravenously to dogs during WBH.
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| Authors | G S Price, R L Page, J E Riviere, J M Cline, D E Thrall |
| Journal | International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group (Int J Hyperthermia) 1995 Jul-Aug Vol. 11 Issue 4 Pg. 531-44 ISSN: 0265-6736 [Print] England |
| PMID | 7594807 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.) |
| Chemical References |
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