Abstract
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.
Footnotes
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Send reprint requests to: Theresa M. Visarius and Bernhard H. Lauterburg, University of Berne, Clinical Pharmacology, Murtenstrasse 35, 3010 Bern, Switzerland. Email, Visarius:theresa{at}mem.unibe.ch. E-mail: Lauterburg, blauterburg{at}ikp.unibe.ch.
- Abbreviations used are::
- IFO
- ifosfamide
- CAA
- chloroacetaldehyde
- CMC
- S-carboxymethyl-L-cysteine
- TDGA
- thiodiglycolic acid (dicarboxymethylsulfide)
- PA
- palmitic acid
- OA
- octanoic acid
- SA
- succinic acid
- PLC
- palmitoyl-L-carnitine
- mesna
- 2-mercaptoethane sulfonate
- TDPA
- 3,3′-thiodipropionic acid
- DNP
- 2,4-dinitrophenol
- Received October 31, 1997.
- Accepted December 15, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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