Pharmacokinetics of methotrexate in the extracellular fluid of brain C6-glioma after intravenous infusion in rats.
OBJECTIVE
Establishment of the pharmacokinetic profile of methotrexate (MTX) in the extracellular fluid (ECF) of a brain C6-glioma in rats.


METHODS
Serial collection of plasma samples and ECF dialysates after i.v. infusion of MTX (50 or 100 mg/kg) for 4 h. HPLC assay.


RESULTS
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.


CONCLUSIONS
High plasma concentrations promote the penetration of MTX into brain tissue. However, free MTX concentrations in tumor ECF remain difficult to predict consistently.
Dukic
S
S
Laboratoire de Pharmacologie et de Pharmacocinétique, U.F.R. de Pharmacie, Université de Reims Champagne Ardenne, Reims, France. sylvain.dukic@univ-reims.fr
Heurtaux
T
T
Kaltenbach
M L
ML
Hoizey
G
G
Lallemand
A
A
Gourdier
B
B
Vistelle
R
R
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002199:Capillary Permeability; D003198:Computer Simulation; D005110:Extracellular Space / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D007262:Infusions, Intravenous; D008297:Male; D008727:Methotrexate / Q000097:blood / Q000493:pharmacokinetics*; D017551:Microdialysis; D009368:Neoplasm Transplantation; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate