Cornford E M, Landon K P
Ther Drug Monit. 1985;7(3):247-54. doi: 10.1097/00007691-198507030-00001.
Brain capillary transit of CI-912 was studied in vivo after a single capillary transit by the intracarotid injection technique. Brain permeability of 14C-drug was measured relative to that of tritiated water, a highly diffusible reference substance. The brain uptake index of CI-912 was measured at concentrations ranging from 5 to 400 micrograms/ml in different regions of the rat brain. Brain uptake was not via a saturable, carrier-mediated mechanism, but was attributable to lipid-mediated transport. The octanol/saline partition coefficient determined in vitro was 3.9, and the blood-brain barrier permeability times surface area product was 0.26 ml min-1 g-1 (in vivo). In the rat brain, efflux of CI-912 after intracarotid injection was found to be minimal, suggesting that this drug is retained in brain tissues. This drug is weakly bound to plasma proteins (75-79% of the drug is freely dialyzable in 4% human serum albumin at 5 micrograms/ml), and protein binding does not affect brain uptake. In contrast, the drug is highly bound to erythrocytes. At concentrations that approximate the predicted optimum therapeutic range (6-40 micrograms/ml), it has been demonstrated that in addition to exchange of plasma-borne drug, erythrocyte-borne CI-912 is able to equilibrate across the blood-brain barrier in the course of a single transcapillary transit. Approximately one half of the drug gaining access to brain in a single transcapillary passage is erythrocyte-borne.
采用颈内动脉注射技术，在单次毛细血管通过后，对CI-912在体内的脑毛细血管转运进行了研究。相对于作为高扩散性参考物质的氚水，测定了14C标记药物的脑通透性。在大鼠脑的不同区域，在5至400微克/毫升的浓度范围内测定了CI-912的脑摄取指数。脑摄取不是通过可饱和的载体介导机制，而是归因于脂质介导的转运。体外测定的辛醇/盐水分配系数为3.9，血脑屏障通透性与表面积的乘积为0.26毫升/分钟·克-1（体内）。在大鼠脑中，发现颈内动脉注射后CI-912的流出极小，表明该药物保留在脑组织中。该药物与血浆蛋白的结合较弱（在5微克/毫升的4%人血清白蛋白中，75-79%的药物可自由透析），并且蛋白结合不影响脑摄取。相反，该药物与红细胞高度结合。在接近预测的最佳治疗范围（6-40微克/毫升）的浓度下，已证明除了血浆携带的药物交换外，红细胞携带的CI-912在单次毛细血管通过过程中能够在血脑屏障上达到平衡。在单次毛细血管通过中进入脑内的药物中，约一半是由红细胞携带的。
