In vivo microdialysis to characterize drug transport in brain tumors: analysis of methotrexate uptake in rat glioma-2 (RG-2)-bearing rats.
Brain microdialysis was applied to sample free methotrexate (MTX) concentrations in brain extracellular fluid of normal and RG-2 glioma-bearing rats. All animals received 50 mg/kg of MTX intra-arterially following which serial blood and interstitial fluid samples were collected for 3 h and measured for MTX by an HPLC assay. Retrodialysis was used to estimate the in vivo recovery of MTX from brain. A linear two-compartment model was fitted to the plasma MTX concentration-time data in both the normal and RG-2 groups. The mean total body clearance and volume of distribution at steady state of MTX varied from 0.90 +/- 0.3 to 0.24 +/- 0.02 l h-1 kg-1 (P < 0.05) and from 0.58 +/- 0.24 to 0.21 +/- 0.16 l kg-1 (P < 0.05) in control and tumor rats, respectively. The significant reductions in clearance and volume of distribution at steady-state were attributed in part to a cachectic state in the RG-2 animals in which total body water was reduced. The mean MTX area under the interstitial fluid concentration-time curve (AUC) was 171.6 +/- 69.14 micrograms min ml-1(control) and 583.5 +/- 296.7 micrograms min ml-1 (brain tumor-bearing rats). The significantly higher AUC values obtained with RG-2 rats compared with control rats may have resulted from high plasma MTX concentrations and a more permeable blood-tumor barrier (BTB). A hybrid physiologically based pharmacokinetic model was used to characterize the mechanisms responsible for the high MTX brain tumor concentrations. In conclusion, a microdialysis technique was successfully utilized to examine the extracellular uptake of MTX in brain. This technique can be a powerful tool to evaluate intracerebral drug kinetics and the delivery of drugs to brain tumors.
Devineni
D
D
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Klein-Szanto
A
A
Gallo
J M
JM
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001923:Brain Chemistry; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D005910:Glioma / Q000378:metabolism*; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics*; D017551:Microdialysis / Q000379:methods*; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate