The disposition of propranolol. 3. Decreased half-life and volume of distribution as a result of plasma binding in man, monkey, dog and rat.
The disposition of propranolol. 3. Decreased half-life and volume of distribution as a result of plasma binding in man, monkey, dog and rat.
复制标题
普萘洛尔的处置。
DOI：
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发表时间：
1973
影响因子：
3.5
通讯作者：
D. Shand
中科院分区：
文献类型：
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作者：
G. H. Evans;A. Nies;D. Shand
用平衡透析法测定了治疗浓度普萘洛尔在人(93.2%)、猴(99.2%)、狗(96.6%)和大鼠(92.2%)的血浆结合率，并与其静脉给药动力学进行了相关分析。在9名受试者中，普萘洛尔从血液中的清除量很高，相对恒定，为1.05升/分钟。表观分布体积(Vdβ)变化2倍，与处置速率常数β成正比。在所研究的所有物种中，随着游离药物浓度的增加，VDβ按猴子：狗：人：大鼠的顺序增加，从而使游离药物的分布量保持恒定。尽管不同物种之间的药物清除量存在很大差异(14-92ml/kg/min)，但由于肝脏萃取率、肝血流相对大小和肝外代谢的不同，这种情况仍然发生。当考虑到可变药物清除的影响时，药物结合力的增加与药物半衰期的减少有关。这种结合的差异部分解释了物种半衰期的差异，并完全解释了静脉给药后人体半衰期的个体间差异。这些数据与血浆结合通过增加药物释放到消除部位的速率而减少心得安的半衰期的假设是一致的。这是因为只有分配的体积取决于流通中的游离药物，而流通中超过游离部分的毒品可供清除器官清除。
The binding of propranolol to plasma has been determined at therapeutic concentrations by equilibrium dialysis in man (93.2%), monkey (99.2%), dog (96.6%) and rat (92.2%) and correlated with its kinetics of disposition after intravenous administration. In nine human subjects the clearance of propranolol from the blood was high and relatively constant at 1.05 liters/min. The apparent volume of distribution (V dβ) which varied 2-fold was proportional to the disposition rate constant, β. In all the species examined Vdβ increased as free drug concentration increased in the order monkey:dog:man:rat, such that the volume of distribution of free drug was constant. This occurred despite large variations in drug clearance among the species (14-92 ml/kg/min), which resulted from differences in hepatic extraction ratio, relative magnitude of liver blood flow and extrahepatic metabolism. When the influence of a variable drug clearance was taken into account, increased drug binding was associated with a decrease in drug half-life. Such differences in binding account in part for species differences in half-life and are entirely responsible for interindividual variation in half-life in man after intravenous administration. These data are consistent with the hypothesis that plasma binding decreases the half-life of propranolol by increasing the rate of drug delivery to its site of elimination. This results because only volume of distribution is dependent on the free drug in the circulation, whereas more than the free fraction of the drug in the circulation is available for clearance by the organs of elimination.