Pharmacokinetics of methotrexate in cerebrospinal fluid and serum after osmotic blood-brain barrier disruption in patients with brain lymphoma.
OBJECTIVE
To evaluate the pharmacokinetics of methotrexate in ventricular cerebrospinal fluid and serum after osmotic blood-brain barrier disruption and intra-arterial administration compared with intravenous or simple intra-arterial infusion in patients with primary central nervous system lymphoma.


METHODS
Serum and ventricular cerebrospinal fluid were sampled after methotrexate administration in 12 patients. Blood-brain barrier disruption was induced on 2 sequential days by mannitol (25%) infusion delivered to the vertebral or internal carotid artery territories followed by intra-arterial methotrexate (dose, 1.4 g/m2; 47 treatments). Sixteen treatments were given without barrier disruption by intravenous (3.5 g/m2; nine treatments) or intra-arterial (2.8 g/m2; seven treatments) infusion.


RESULTS
Ventricular cerebrospinal fluid-methotrexate peak levels after blood-brain barrier disruption of the vertebral and the internal carotid arteries territories were 19.3 +/- 2.9 and 8.5 +/- 0.7 micromol/L (P < .001), and the area under the curve from time 0 to infinity was 178.0 +/- 21.3 and 110.0 +/- 12.4 [micromol/L x h, respectively (P < .01). No significant differences were observed in serum levels. After intra-arterial infusion was performed without disruption, the serum peak level was higher than that achieved by intravenous treatment (518.2 +/- 67.7 versus 180.6 +/- 31.8 micromol/L; P < .001). No differences were observed in cerebrospinal fluid concentrations, which dropped below 1 micromol/L at 6 hours. The cerebrospinal fluid/serum ratio [AUC(%)] of methotrexate after blood-brain barrier disruption was three to four times greater than that by systemic administration.


CONCLUSIONS
Enhanced methotrexate delivery to the central nervous system can be attained by intra-arterial administration combined with osmotic disruption of the blood-brain barrier compared with simple intra-arterial or intravenous administration.
Zylber-Katz
E
E
Division of Medicine, the Neuro-Oncology Center, Hadassah University Hospital, Jerusalem, Israel. esterzk@hadassah.org.il
Gomori
J M
JM
Schwartz
A
A
Lossos
A
A
Bokstein
F
F
Siegal
T
T
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D002552:Cerebral Ventricles; D005260:Female; D006801:Humans; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D008223:Lymphoma / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D008875:Middle Aged; D009995:Osmosis
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate