Study on Drug Distribution into Brain and Cerebrospinal Fluid by Microdialysis

采用微透析法对大鼠静脉注射咖啡因后脑组织和脑脊液中咖啡因浓度的时序性进行了研究。测定微透析液中咖啡因的回收率、透析液中咖啡因与脑组织或脑脊液中咖啡因的浓度比。在5种不同的咖啡因稳态血浆浓度(0.1~280nmol/ml)和不同的透析液收集时间(30~10min)下，咖啡因的回收率保持恒定。脑组织和脑脊液的平均回收率分别为10.9%和13.1%。因此，微透析法被证明是测定组织和生物液体中药物浓度的有效方法，时间分辨率大于30s。然后，微透析法被应用于静脉推注后脑和脑脊液中咖啡因浓度的时序测定。脑和脑脊液中咖啡因的估计浓度分别与直接测定离体脑和脑脊液中的咖啡因浓度相同。咖啡因从血浆到脑和脑脊液的转运采用改进的两室模型进一步进行了药代动力学分析。在这个动力学模型中，由于在活体实验中没有检测到咖啡因的相互转移，因此忽略了咖啡因在脑脊液和脑之间的转移。计算的曲线与观察到的血浆、脑和脑脊液中的咖啡因浓度很好地吻合。

The usefulness of microdialysis was examined for the chronological determination of caffeine concentration in the brain and cerebrospinal fluids (CSF) following intravenous administration of caffeine in rats. The recovery percent of caffeine by microdialysis, the concentration ratio of caffeine in the dialysate against that in the brain tissue or CSF was determined. The recovery percent was proved to be constant at 5 different steady -state plasma concentrations of caffeine (0.1 - 280 nmol/ml) and in different collecting periods of dialysate ranging from 30 s to 10 min. The mean recovery percent in the brain and CSF were 10.9 and 13.1%, respectively. Thus, microdialysis was proved useful for determination of drug concentration in the tissue and bilogical fluids with time resolution of more than 30 s.The microdialysis method was then applied for the chronological determination of caffeine concentration in the brain and CSF following intravenous bolus administration. The estimated caffeine concentration in the brain and CSF was as the same as those obtained by direct determination in isolated brain and CSF, respectively. Transfer of caffeine from plasma to brain and CSF were further pharmacokinetically analyzed using a modified 2-compartment model. In this kinetic model, the transfer of caffeine between the CSF and brain was neglected, since the mutual transfer of caffeine was not detected in vivo experiments. Calculated curves were well fitted on observed caffeine concentrations in the plasma, brain and CSF.