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Vol. 26, Issue 3, 193-196, March 1998

ACCELERATED COMMUNICATION
Thiodiglycolic Acid is Excreted by Humans Receiving Ifosfamide and Inhibits Mitochondrial Function in Rats

Theresa M. Visarius, Heinz Bähler, Adrian Küpfer, Thomas Cerny, and Bernhard H. Lauterburg

Clinical Pharmacology (T.M.V., A.K., B.H.L), University of Berne; and Medical Oncology (H.B., T.C.), University Hospital

Thiodiglycolic acid has been identified as a major metabolite of the anticancer drug ifosfamide in humans. Patients treated with 12-16 g ifosfamide/m2·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 mmol 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. Thiodiglycolic acid (50mg/kg) administered to rats inhibited the carnitine-dependent oxidation of [1-14C]palmitic acid by 55%, but affected neither the oxidation of [1-14C]octanoic acid, which is carnitine-independent, nor the oxidation of [1,4-14C]succinic acid, a marker of Kreb's cycle activity. Additionally, thiodiglycolic acid (30µM) 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 chemotherapy.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 1998 by the American Society for Pharmacology and Experimental Therapeutics.