Hamberger C, Urien S, Essassi D, Grimaldi B, Barre J, Taiclet A, Thenot J P, Tillement J P
Biochem Pharmacol. 1987 Aug 15;36(16):2641-5. doi: 10.1016/0006-2952(87)90545-4.
Brain extraction of two antiepileptic compounds, progabide and its acid metabolite, SL 75102, was investigated using the carotid injection technique in the rat. The extent to which drug binding to plasma proteins could inhibit the brain extraction was measured. Equilibrium dialysis at 4 degrees showed that both drugs were highly bound to human serum proteins, mainly to serum albumin. Progabide is also bound to red blood cells and to lipoproteins. The free dialyzable drug fraction was inversely related to the protein concentration. Similarly, the brain extraction of the drugs in the presence of either albumin, or red blood cells for progabide was inversely related to their respective concentrations. However, the rat brain extraction of both drugs was higher than expected from the in vitro measurement of dialyzable fraction. Furthermore, despite a significant degree of progabide binding to lipoproteins, no significant reduction in the brain extraction of the drug was observed. These data indicate that the amount of circulating progabide or SL 75102 available for penetration in a peripheral tissue such as brain exceeds the dialyzable fraction of drug. However, the in vivo exchangeable drug fraction still parallels the dialyzable fraction, except if the drug is lipoprotein-bound.
采用颈动脉注射技术在大鼠体内研究了两种抗癫痫化合物普罗加比及其酸性代谢物SL 75102的脑摄取情况。测定了药物与血浆蛋白结合对脑摄取的抑制程度。4℃下的平衡透析表明，两种药物都与人类血清蛋白高度结合，主要是与血清白蛋白结合。普罗加比还与红细胞和脂蛋白结合。可透析的游离药物分数与蛋白质浓度呈负相关。同样，在存在白蛋白或普罗加比的红细胞时，药物的脑摄取与它们各自的浓度呈负相关。然而，两种药物在大鼠脑中的摄取高于根据可透析分数的体外测量所预期的值。此外，尽管普罗加比与脂蛋白有显著程度的结合，但未观察到该药物脑摄取的显著降低。这些数据表明，可用于渗透到外周组织如脑内的循环普罗加比或SL 75102的量超过了药物的可透析分数。然而，体内可交换的药物分数仍然与可透析分数平行，除非药物与脂蛋白结合。
