Penetration of ifosfamide and its active metabolite 4-OH-ifosfamide into cerebrospinal fluid of patients with CNS malignancies.
OBJECTIVE
The aim of this study was to examine the penetration of ifosfamide (IFO) and 4-hydroxy-ifosfamide (4-OH-IFO) into the CSF of human adults and to evaluate the influence of blood-CSF barrier (BCB) function.


METHODS
In 12 adult patients with a malignant CNS disease treated with IFO 1,300-2,000 mg/m(2)/d as a 3-hour intravenous infusion, 17 CSF samples were collected within 10 min after the end of IFO infusion. In 8 of these patients, the CSF was obtained in up to 5 sequential 2-ml portions to detect a potential caudocranial concentration gradient. Additionally, blood was collected before treatment and immediately following IFO infusion.


RESULTS
IFO was detected in all 17 CSF samples at a median concentration of 79.24 μmol/l (39.27-176.73) and a median CSF/plasma ratio of 0.38 (0.18-0.72). 4-OH-IFO was detected in 11 CSF samples from 7 patients at a median concentration of 4.1 μmol/l (2.44-36.03) and a median CSF/plasma ratio of 3.07 (0.62-29.12). 4-OH-IFO was undetectable in 6 CSF samples from 5 patients and in one plasma sample. Both CSF drug concentrations and their CSF/plasma quotients neither correlated with steroid comedication nor with albumin quotients (QAlb).


CONCLUSIONS
Both IFO and 4-OH-IFO can penetrate into the CSF of human adults without a correlation to CSF turnover. In contrast to IFO, 4-OH-IFO CSF penetration is not reliable with levels ranging between undetectable and exceeding those in the corresponding plasma.
Kiewe
Philipp
P
Department of Hematology, Oncology and Transfusion Medicine, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Hindenburgdamm 30/31, 12200 Berlin, Germany. philipp.kiewe@charite.de
Neumann
Martin
M
Wagner
Thomas
T
Seyfert
Sepp
S
Albrecht
Heike
H
Thiel
Eckhard
E
Korfel
Agnieszka
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000378:metabolism; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010539:Permeability
D018906:Antineoplastic Agents, Alkylating; C039771:4-hydroxyifosfamide; D007069:Ifosfamide