1. Pharmacokinetics of methotrexate in cerebrospinal fluid and serum after osmotic blood-brain barrier disruption in patients with brain lymphoma.
- Author
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Zylber-Katz E, Gomori JM, Schwartz A, Lossos A, Bokstein F, and Siegal T
- Subjects
- Adult, Aged, Antimetabolites, Antineoplastic blood, Antimetabolites, Antineoplastic cerebrospinal fluid, Brain Neoplasms drug therapy, Cerebral Ventricles, Female, Humans, Infusions, Intra-Arterial, Infusions, Intravenous, Lymphoma drug therapy, Male, Methotrexate blood, Methotrexate cerebrospinal fluid, Middle Aged, Osmosis, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic pharmacokinetics, Blood-Brain Barrier, Brain Neoplasms blood, Brain Neoplasms cerebrospinal fluid, Lymphoma blood, Lymphoma cerebrospinal fluid, Methotrexate administration & dosage, Methotrexate pharmacokinetics
- Abstract
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., 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.
- Published
- 2000
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