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/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 (30 microM) 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.
Visarius
T M
TM
Clinical Pharmacology, University of Berne, Berne, Switzerland.
Bähler
H
H
Küpfer
A
A
Cerny
T
T
Lauterburg
B H
BH
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000378:metabolism; D002210:Caprylates / Q000378:metabolism; D002331:Carnitine / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D006801:Humans; D007069:Ifosfamide / Q000009:adverse effects / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D019308:Palmitic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019802:Succinic Acid / Q000378:metabolism; D013864:Thioglycolates / Q000494:pharmacology* / Q000652:urine*
D018906:Antineoplastic Agents, Alkylating; D002210:Caprylates; D013864:Thioglycolates; D019308:Palmitic Acid; C010518:thiodiacetic acid; D019802:Succinic Acid; D002334:Carnitine O-Palmitoyltransferase; C031492:octanoic acid; D002331:Carnitine; D007069:Ifosfamide