Accelerated Communication Thiodiglycolic Acid Is Excreted by Humans Receiving Ifosfamide and Inhibits Mitochondrial Function in Rats

Thiodiglycolic acid has been identified as a major metabolite of the anticancer drug ifosfamide in humans. Patients treated with 12–16 g ifosfamide/mzday excreted thiodiglycolic acid ranging from 0.10 6 0.02 mmol on the first day of therapy, to a maximum of 3.27 6 0.15 mmol on the fourth day of ifosfamide infusion. This amounted to 5.4 6 0.2% of the administered dose of ifosfamide appearing as thiodiglycolic acid in urine during a 5 days’ continuous ifosfamide infusion. Thiodiglycolic acid (50mg/kg) administered to rats inhibited the carnitine-dependent oxidation of [1-C]palmitic acid by 55%, but affected neither the oxidation of [1-C]octanoic acid, which is carnitine-independent, nor the oxidation of [1,4-C]succinic acid, a marker of Kreb’s cycle activity. Additionally, thiodiglycolic acid (30mM) inhibited oxidation of palmitic acid but not palmitoyl-L-carnitine in isolated rat liver mitochondria, indicating that it either sequesters carnitine or inhibits carnitine palmitoyltransferase I. This study elucidates a specific mitochondrial dysfunction induced by thiodiglycolic acid which may contribute to the adverse effects associated with ifosfamide