Devineni D, Klein-Szanto A, Gallo J M
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Cancer Chemother Pharmacol. 1996;38(6):499-507. doi: 10.1007/s002800050518.
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.
采用脑微透析技术采集正常大鼠和荷RG - 2胶质瘤大鼠脑细胞外液中游离甲氨蝶呤（MTX）的浓度。所有动物经动脉内给予50mg/kg的MTX，随后在3小时内连续采集血液和间质液样本，并通过高效液相色谱法测定MTX含量。采用逆向透析法估算MTX在脑内的体内回收率。对正常组和RG - 2组的血浆MTX浓度 - 时间数据拟合线性二室模型。MTX的平均总体清除率和稳态分布容积在对照大鼠和荷瘤大鼠中分别从0.90±0.3降至0.24±0.02 l h⁻¹ kg⁻¹（P < 0.05）和从0.58±0.24降至0.21±0.16 l kg⁻¹（P < 0.05）。稳态清除率和分布容积的显著降低部分归因于RG - 2动物的恶病质状态，其体内总水量减少。间质液浓度 - 时间曲线下MTX的平均面积（AUC）在对照组为171.6±69.14μg min ml⁻¹，在荷脑肿瘤大鼠中为583.5±296.7μg min ml⁻¹。与对照大鼠相比，RG - 2大鼠获得的显著更高的AUC值可能是由于血浆MTX浓度高以及血 - 肿瘤屏障（BTB）通透性更高所致。采用基于生理的混合药代动力学模型来表征导致MTX在脑肿瘤中高浓度的机制。总之，成功利用微透析技术检测了脑内MTX的细胞外摄取。该技术可成为评估脑内药物动力学和药物向脑肿瘤递送的有力工具。
