Metabolism of ifosfamide during a 3 day infusion.
Urinary drug metabolites were measured in 21 patients receiving ifosfamide by continuous infusion over 3 days. Mean values for the proportion of drug excreted as parent compound, 2-dechloroethylifosfamide (2-DC), 3-dechloroethylifosfamide (3-DC), carboxyifosfamide (CX) and ifosforamide mustard (IPM) were 19, 6, 10, 7 and 8% of dose respectively. The proportion of urinary drug products in the form of ifosfamide fell considerably over the course of the 3 days. This was mirrored by an increase in the proportion of 2-DC, 3-DC and CX. The proportion in the form of IPM, however, remained unchanged. With successive cycles the amount of 2-DC and IPM increased by about 10% per course. A very wide variation in the amount of each metabolite was reproducibly seen between patients, but no evidence for a genetic polymorphism was found. Urinary dechloroethyl metabolites correlated positively with each other and negatively with CX. Although autoinduction increases 'activation' of ifosfamide when given over 3 days, our evidence suggests that competing metabolic pathways prevent an increase in the amount of active metabolite formed.
Hartley
J M
JM
Department of Medical Oncology, University College London Medical School, Middlesex Hospital, UK.
Hansen
L
L
Harland
S J
SJ
Nicholson
P W
PW
Pasini
F
F
Souhami
R L
RL
D000230:Adenocarcinoma / Q000652:urine; D002855:Chromatography, Thin Layer; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism* / Q000652:urine; D008297:Male; D018242:Neuroectodermal Tumors, Primitive / Q000652:urine; D012516:Osteosarcoma / Q000652:urine; D010752:Phosphoramide Mustards; D012208:Rhabdomyosarcoma / Q000652:urine; D012512:Sarcoma, Ewing / Q000652:urine; D013997:Time Factors
D010752:Phosphoramide Mustards; C064446:carboxyifosfamide; C027061:isophosphamide mustard; D007069:Ifosfamide