PHARMACOKINETICS AND TOXICITY OF ORAL AND INTRAVENOUS LONIDAMINE IN DOGS

Plasma lonidamine concentration and toxicity were investigated in dogs receiving 100, 200, 400, 800, 1200 mg/m(2) orally twice daily for 30 days and in dogs receiving single intravenous doses of 200, 400, 800, 1200 mg/m(2). Physical or laboratory signs of toxicity were not observ ed in dogs receiving oral lonidamine, but severe vomiting and signs of acute hepatic and pancreatic toxicity were observed in dogs receiving intravenous doses that exceeded 400 mg/m(2). The area under the lonid amine concentration versus time curve (AUC) in dogs receiving 200, 400 , and 800 mg/m(2) of lonidamine intravenously was a 1.8-, 3.3-, and 8. 7-fold higher than in dogs receiving oral lonidamine. This suggests th at the bioavailability of oral lonidamine may be limited. However, cen trilobular hepatocellular swelling and vacuolation were observed in do gs receiving oral lonidamine. Serum alanine aminotransferase (ALT) act ivity was increased in dogs receiving intra-venous lonidamine. These f indings suggest that lonidamine is hepatotoxic in dogs. However, serum ALT was increased in only 1/4 dogs receiving 400 mg/m(2) of lonidamin e intravenously and plasma concentration were within the range capable of sensitizing hyperthermia and chemotherapy. Therefore, this dose an d route appears to be a viable and controllable method for prospective quantification of lonidamine interaction with systemic chemotherapy a nd/or hyperthermia.