Pharmacokinetics and toxicity of oral and intravenous lonidamine in dogs

Abstract

Plasma lonidamine concentration and toxicity were investigated in dogs receiving 100, 200, 400, 800, 1200 mg/m2 orally twice daily for 30 days and in dogs receiving single intravenous doses of 200, 400, 800, 1200 mg/m2. Physical or laboratory signs of toxicity were not observed 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/m2. The area under the lonidamine concentration versus time curve (AUC) in dogs receiving 200, 400, and 800 mg/m2 of lonidamine intravenously was a 1.8-, 3.3-, and 8.7-fold higher than in dogs receiving oral lonidamine. This suggests that the bioavailability of oral lonidamine may be limited. However, centrilobular hepatocellular swelling and vacuolation were observed in dogs receiving oral lonidamine. Serum alanine aminotransferase (ALT) activity was increased in dogs receiving intra-venous lonidamine. These findings suggest that lonidamine is hepatotoxic in dogs. However, serum ALT was increased in only 1/4 dogs receiving 400 mg/m2 of lonidamine intravenously and plasma concentration were within the range capable of sensitizing hyperthermia and chemotherapy. Therefore, this dose and route appears to be a viable and controllable method for prospective quantification of lonidamine interaction with systemic chemotherapy and/or hyperthermia.

Discovery of N-Hydroxyindole-Based Inhibitors of Human Lactate Dehydrogenase Isoform A (LDH-A) as Starvation Agents against Cancer Cells

“…Subsequent hydrolysis with aqueous 2 N LiOH in a THF/MeOH mixture afforded the final products 1a-k. Noncommercially available precursors 2j and 2k were respectively prepared by a Pd-catalyzed crosscoupling of 5-iodo-2-methyl-3-nitrobenzotrifluoride 5 38 with phenylboronic acid under ligand-free conditions in a microwave reactor 39 and by a zinc-promoted addition of sodium azide 40 to benzonitrile 6. An example of O-methylated NHI (8) was also synthesized to verify the importance of the free OH group in the enzyme inhibition assays. For this purpose, NHI 4i was treated with iodomethane and DBU in THF at room temperature to give ester 7, which was eventually hydrolyzed to compound 8.…”

Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

“…Lonidamine reached phase III of clinical trials [158,159,160], however, there has not been further advancement with this agent recently. Increased toxicity to the pancreas and liver by Lonidamine has been reported in an animal model [161]. …”

Tumor glycolysis as a target for cancer therapy: progress and prospects

“…Lonidamine is an inhibitor of HKII and has completed phase III trial. However its clinical success has so far been impaired by significant pancreatic and hepatic toxicities [88]. Similarly, another glucose analog 2-deoxyglucose (2-DG) also showed promising anticancer effects in preclinical models [89].…”