Pharmacokinetics of methotrexate in the extracellular fluid of brain C6-glioma after intravenous infusion in rats

• Published in: Pharmaceutical research Vol. 16; no. 8; pp. 1219 - 1225
• Main Authors: DUKIC, S, HEURTAUX, T, KALTENBACH, M. L, HOIZEY, G, LALLEMAND, A, GOURDIER, B, VISTELLE, R
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 01.08.1999; Springer Nature B.V
• Subjects: Animals; Antimetabolites, Antineoplastic - blood; Antimetabolites, Antineoplastic - pharmacokinetics; Antineoplastic agents; Biological and medical sciences; Blood-brain barrier; Brain cancer; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Capillary Permeability; Catheters; Computer Simulation; Extracellular Space - metabolism; General aspects; Glioma - metabolism; Glioma - pathology; Infusions, Intravenous; Laboratory animals; Male; Medical sciences; Methotrexate - blood; Methotrexate - pharmacokinetics; Microdialysis; Neoplasm Transplantation; Nervous system; Permeability; Pharmacokinetics; Pharmacology. Drug treatments; Plasma; Rats; Rats, Wistar; Tissue Distribution; Tumor Cells, Cultured; France; Paris France; Antineoplastic agent; Nervous system diseases; Intravenous administration; Rat; Rodentia; Malignant tumor; Bioavailability; Permeability; In vitro; Blood plasma; Malignant glioma; In vivo; Extracellular fluid; Vertebrata; Mammalia; Microdialysis; Simulation; Animal; Central nervous system disease; Distribution; Methotrexate; Pharmacokinetics; Tumor cell
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1018945529611

Establishment of the pharmacokinetic profile of methotrexate (MTX) in the extracellular fluid (ECF) of a brain C6-glioma in rats. Serial collection of plasma samples and ECF dialysates after i.v. infusion of MTX (50 or 100 mg/kg) for 4 h. HPLC assay. Histological studies revealed the presence of inflammation, edema, necrosis, and hemorrhage in most animals. In vivo recovery (reverse dialysis) was 10.8 +/- 5.3%. MTX concentrations in tumor ECF represented about 1-2% of the plasma concentrations. Rapid equilibration between MTX levels in brain tumor ECF and plasma. ECF concentrations almost reached steady-state by the end of the infusion (4 h), then decayed in parallel with those in plasma. Doubling of the dose did not modify MTX pharmacokinetic parameters (t1/2alpha, t1/2beta, MRT, fb, Vd, and CL(T)), except for a 1.7-fold increase of AUC(Plasma) and a 3.8-fold increase in AUC(ECF), which resulted in a 2.3-fold increase in penetration (AUC(ECF)/AUC(Plasma)). In spite of an important interindividual variability, a relationship between MTX concentrations in plasma and tumor ECF could be established from mean pharmacokinetic parameters. High plasma concentrations promote the penetration of MTX into brain tissue. However, free MTX concentrations in tumor ECF remain difficult to predict consistently.