Premium
Pharmacokinetics of methotrexate in cerebrospinal fluid and serum after osmotic blood‐brain barrier disruption in patients with brain lymphoma
Author(s) -
ZylberKatz Ester,
Gomori J. Moshe,
Schwartz Allan,
Lossos Alexander,
Bokstein Felix,
Siegal Tali
Publication year - 2000
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2000.106932
Subject(s) - cerebrospinal fluid , medicine , methotrexate , blood–brain barrier , pharmacokinetics , anesthesia , arterial blood , central nervous system , urology
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/m 2 ; 47 treatments). Sixteen treatments were given without barrier disruption by intravenous (3.5 g/m 2 ; nine treatments) or intra‐arterial (2.8 g/m 2 ; 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 μmol/L ( P < .001), and the area under the curve from time 0 to infinity was 178.0 ± 21.3 and 110.0 ± 12.4 μmol/L · 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 μmol/L; P < .001). No differences were observed in cerebrospinal fluid concentrations, which dropped below 1 μmol/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. Conclusion 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. Clinical Pharmacology & Therapeutics (2000) 67 , 631–641; doi: 10.1067/mcp.2000.106932