RT Journal Article
SR Electronic
T1 Thiodiglycolic Acid is Excreted by Humans Receiving Ifosfamide and Inhibits Mitochondrial Function in Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 193
OP 196
VO 26
IS 3
A1 Theresa M. Visarius
A1 Heinz Bähler
A1 Adrian Küpfer
A1 Thomas Cerny
A1 Bernhard H. Lauterburg
YR 1998
UL http://dmd.aspetjournals.org/content/26/3/193.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics