Sugihara N, Furuno K, Kita N, Murakami T, Yata N
Faculty of Pharmaceutical Sciences, Fukuyama University, Hiroshima, Japan.
Chem Pharm Bull (Tokyo). 1991 Oct;39(10):2671-3. doi: 10.1248/cpb.39.2671.
Plasma protein binding of weakly basic drugs such as propranolol and quinidine was determined in rats with carbon tetrachloride (CCl4)-induced hepatic disease. Free fractions of propranolol and quinidine in the plasma of rats at 24 h after CCl4-intoxication were decreased by 41 and 30%, respectively, compared to those of control rats. An addition of Tris (butoxyethyl) phosphate (TBEP), a specific displacer for basic drugs from alpha 1-acid glycoprotein (AGP), to the plasma increased the free fractions of the basic drugs, resulting in no difference in the extent of the plasma free fraction of each drug between control and CCl4-intoxicated rats. Plasma concentration of AGP in CCl4-intoxicated rats was elevated 2.7-fold of that in control rats at 24 h after the CCl4 intoxication and reached a peak of 4.8-fold elevation at 48 h. A regression analysis revealed a high degree of positive correlation between ratios of bound to free fraction of propranolol and plasma concentrations of AGP. These results suggest that the plasma protein binding of the basic drugs was increased mainly due to the rise in the plasma AGP concentration in CCl4-intoxicated rats.
在四氯化碳（CCl4）诱导的肝病大鼠中，测定了普萘洛尔和奎尼丁等弱碱性药物的血浆蛋白结合情况。与对照大鼠相比，CCl4中毒后24小时大鼠血浆中普萘洛尔和奎尼丁的游离分数分别降低了41%和30%。向血浆中添加磷酸三（丁氧乙基）酯（TBEP），一种从α1-酸性糖蛋白（AGP）上置换碱性药物的特异性置换剂，可增加碱性药物的游离分数，导致对照大鼠和CCl4中毒大鼠之间每种药物的血浆游离分数程度没有差异。CCl4中毒大鼠在CCl4中毒后24小时血浆AGP浓度升高至对照大鼠的2.7倍，并在48小时达到4.8倍升高的峰值。回归分析显示普萘洛尔结合与游离分数之比与血浆AGP浓度之间存在高度正相关。这些结果表明，在CCl4中毒大鼠中，碱性药物的血浆蛋白结合增加主要是由于血浆AGP浓度升高所致。
