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 a nticancer drug ifosfamide in humans. Patients treated with 12-16 g ifo sfamide/m(2) day excreted thiodiglycolic acid ranging from 0.10 +/- 0. 02 mmol on the first day of therapy, to a maximum of 3.27 +/- 0.15 mmo l on the fourth day of ifosfamide infusion. This amounted to 5.4 +/- 0 .2% of the administered dose of ifosfamide appearing as thiodiglycolic acid in urine during a 5 days' continuous ifosfamide infusion. Thiodi glycolic acid (50mg/kg) administered to rats inhibited the carnitine-d ependent oxidation of [1-C-14]palmitic acid by 55%, but affected neith er the oxidation of [1-C-14]octanoic acid, which is carnitine-independ ent, nor the oxidation of [1,4-C-14]succinic acid, a marker of Kreb's cycle activity. Additionally, thiodiglycolic acid (30 mu M) inhibited oxidation of palmitic acid but not palmitoyl-1-carnitine in isolated r at liver mitochondria, indicating that it either sequesters carnitine or inhibits carnitine palmitoyltransferase I. This study elucidates a specific mitochondrial dysfunction induced by thiodiglycolic acid whic h may contribute to the adverse effects associated with ifosfamide che motherapy.