title: Effect of whole-body hyperthermia on the pharmacokinetics and toxicity of lonidamine in dogs.
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.
authors.affiliation: Department of Companion Animal and Special Services Medicine, College of Veterinary Medicine, North Carolina State University, Raleigh 27606, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Price
authors.forename: R L
authors.initials: RL
authors.lastname: Page
authors.forename: J E
authors.initials: JE
authors.lastname: Riviere
authors.forename: J M
authors.initials: JM
authors.lastname: Cline
authors.forename: D E
authors.initials: DE
authors.lastname: Thrall
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000681:Amylases / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D001663:Bilirubin / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002245:Carbon Dioxide / Q000097:blood; D003402:Creatine Kinase / Q000097:blood; D004285:Dogs; D006979:Hyperthermia, Induced; D007008:Hypokalemia / Q000209:etiology; D007191:Indazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D012798:Sialorrhea / Q000209:etiology; D014508:Urea / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D001786:Blood Glucose; D007191:Indazoles; D002245:Carbon Dioxide; D014508:Urea; D000410:Alanine Transaminase; D003402:Creatine Kinase; D000469:Alkaline Phosphatase; D000681:Amylases; D001663:Bilirubin; C016371:lonidamine