Leisen Christiane, Langguth Peter, Herbert Bernd, Dressler Cornelia, Koggel Annette, Spahn-Langguth Hilde
Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, D-06120 Hall Saale.
Pharm Res. 2003 May;20(5):772-8. doi: 10.1023/a:1023437603555.
Distribution to the effect site is a prerequisite for the therapeutic effect and determined by physicochemical properties and affinities to inside- and outside-directed membrane transporters. Based on the hypothesis that lipophilic esters of the GABA-derivative baclofen have a higher affinity to brain tissue, baclofen esters (methyl, ethyl, 1-propyl, 2-propyl, butyl) were studied regarding their penetration through the blood-brain barrier and their affinities to P-glycoprotein (P-gp).
Octanol-water distribution coefficients (D) served as lipophilicity parameters. Blood and brain concentrations of baclofen and its methyl ester were determined in vivo in rats following intraperitoneal administration. Affinities to P-gp were evaluated using a radioligand binding assay based on P-gp-overexpressing cells and [3H]-talinolol as radioligand.
Log D values for baclofen and ester derivatives were -0.96 (baclofen), 0.48 (methyl), 0.77 (ethyl), 1.31 (1-propyl), 1.27 (2-propyl), and 1.42 (butyl). In-vitro studies yielded negligible affinity of baclofen to P-gp, whereas IC50-values for the esters ranged between 1300 microM (methyl) and 290 microM (2-propyl). Affinity parameters correlated well with the lipophilicity parameters.
Despite the P-gp affinity, brain concentrations of methyl ester were significantly higher than those of baclofen, however, baclofen levels following administration of the ester were smaller than with baclofen administration indicating only partial hydrolysis.
药物分布到效应部位是产生治疗效果的前提条件，它由药物的理化性质以及对内向和外向膜转运体的亲和力决定。基于γ-氨基丁酸衍生物巴氯芬的亲脂性酯对脑组织具有更高亲和力这一假设，对巴氯芬酯（甲酯、乙酯、1-丙酯、2-丙酯、丁酯）的血脑屏障穿透性及其对P-糖蛋白（P-gp）的亲和力进行了研究。
采用正辛醇-水分配系数（D）作为亲脂性参数。腹腔注射后，在大鼠体内测定巴氯芬及其甲酯的血液和脑组织浓度。基于过表达P-gp的细胞和[3H]-他林洛尔作为放射性配体，通过放射性配体结合试验评估对P-gp的亲和力。
巴氯芬及其酯衍生物的log D值分别为-0.96（巴氯芬）、0.48（甲酯）、0.77（乙酯）、1.31（1-丙酯）、1.27（2-丙酯）和1.42（丁酯）。体外研究表明巴氯芬对P-gp的亲和力可忽略不计，而酯类的IC50值在1300微摩尔（甲酯）至290微摩尔（2-丙酯）之间。亲和力参数与亲脂性参数相关性良好。
尽管甲酯对P-gp有亲和力，但其脑组织浓度显著高于巴氯芬，然而，给予酯类后巴氯芬的水平低于给予巴氯芬时，表明仅发生了部分水解。
