Influence of C6 and CNS1 brain tumors on methotrexate pharmacokinetics in plasma and brain tissue.
OBJECTIVE
Comparison of the influence of two different brain tumors (C6 and CNS1 glioma) on methotrexate (MTX) disposition in plasma, brain, and tumor tissue extracellular fluid (ECF).


METHODS
Serial collection of plasma samples and brain ECF dialysates after i.v. bolus administration of MTX (50 mg kg(-1)) for 4 h. Quantitation of MTX concentrations by HPLC-UV.


RESULTS
Histological studies revealed a 3-fold higher number of blood vessels in CNS1 than in C6 tumor tissue. In vivo recoveries (reverse dialysis) were significantly different in tumor tissue (C6: 8.0 +/- 3.8%; CNS1: 4.9 +/- 2.5%), and in the contralateral hemisphere (C6: 6.0 +/- 4.0%; CNS1: 3.9 +/- 2.5%) between the two tumors. Area under the concentration-time curve (AUC) in plasma was 30% higher in CNS1 than in C6 due to a lower systemic clearance. Maximum MTX levels in brain tumor ECF were significantly higher in CNS1 than in C6, and decreased faster in CNS1 than in C6 tumor-bearing rats. Penetration in tumor ECF (AUC(ECF)/AUC(Plasma) ratio) was similar in CNS1 and C6. MTX concentrations in contralateral hemisphere were significantly lower than in tumor tissue and dependent on tumor model.


CONCLUSIONS
C6 and CNS1 brain tumors have a distinct yet highly variable impact on MTX penetration in brain and brain tumor ECF.
Dukic
Sylvain F
SF
Laboratoire de Pharmacologie et de Pharmacocinétique, U.F.R. de Pharmacie, Université de Reims Champagne Ardenne, Reims, France. sylvain.dukic@univ-reims.fr
Kaltenbach
Matthieu L
ML
Heurtaux
Tony
T
Hoizey
Guillaume
G
Lallemand
Aude
A
Vistelle
Richard
R
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000032:analysis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000502:physiology; D001923:Brain Chemistry; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D015314:Dialysis Solutions / Q000737:chemistry; D004195:Disease Models, Animal; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000032:analysis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017551:Microdialysis; D051381:Rats; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D015314:Dialysis Solutions; D008727:Methotrexate