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 metho trexate administration in 12 patients. Blood-brain barrier disruption was i nduced on 2 sequential days by mannitol (25%) infusion delivered to the ver tebral or internal carotid artery territories followed by intra-arterial me thotrexate (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 blo od-brain barrier disruption of the vertebral and the internal carotid arter ies territories were 19.3 +/- 2.9 and 8.5 +/- 0.7 mu mol/L (P <.001), and t he area under the curve from time 0 to infinity was 178.0 +/- 21.3 and 110. 0 +/- 12.4 mu mol/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 i ntravenous treatment (518.2 +/- 67.7 versus 180.6 +/- 31.8 mu mol/L; P <.00 1). No differences were observed in cerebrospinal fluid concentrations, whi ch dropped below 1 mu mol/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 ca n be attained by intra-arterial administration combined with osmotic disrup tion of the blood-brain barrier compared with simple intraarterial or intra venous administration.