Belknap S M, Nelson J E, Ruo T I, Frederiksen M C, Worwag E M, Shin S G, Atkinson A J
Clinical Pharmacology Center, Northwestern University Medical School, Chicago, Illinois.
J Pharmacol Exp Ther. 1987 Dec;243(3):963-9.
Theophylline distribution kinetics were studied after i.v. injection in five anesthetized dogs. [14C]Urea and inulin were injected simultaneously as reference compounds to measure body fluid spaces and to calculate compartmental blood flows and permeability coefficient-surface area products for transcapillary exchange. The distribution of all three compounds was modeled with three-compartment systems in which the central compartment corresponds to intravascular space. The total volume of theophylline distribution averaged 0.72 +/- 0.09 liters/kg (+/- S.D.), indicating net tissue binding as reflected in a tissue/intracellular water partition coefficient of 1.17 +/- 0.10. Cardiac output measurements averaged 4.78 +/- 0.95 liters/min and were similar to the sum of compartmental blood flows estimated from the intercompartmental clearances of urea and inulin (4.62 +/- 1.10 liters/min) and to the sum of theophylline intercompartmental clearances (5.10 +/- 1.29 liters/min). Theophylline intercompartmental clearance to each peripheral compartment was faster than expected from its free-water diffusion coefficient and was similar to estimated compartmental blood flow. It is possible that theophylline transcapillary exchange is carrier mediated and that its rapidity contributes to the frequency of adverse reactions after i.v. administration of this drug.
在五只麻醉犬静脉注射后研究了茶碱的分布动力学。同时注射[14C]尿素和菊粉作为参考化合物，以测量体液空间，并计算跨毛细血管交换的隔室血流量和渗透系数-表面积乘积。所有三种化合物的分布均用三室系统建模，其中中央隔室对应于血管内空间。茶碱分布的总体积平均为0.72±0.09升/千克（±标准差），表明存在净组织结合，反映在组织/细胞内水分配系数为1.17±0.10。心输出量测量平均值为4.78±0.95升/分钟，与根据尿素和菊粉的隔室间清除率估计的隔室血流量之和（4.62±1.10升/分钟）以及茶碱隔室间清除率之和（5.10±1.29升/分钟）相似。茶碱向每个外周隔室的隔室间清除率比根据其自由水扩散系数预期的要快，并且与估计的隔室血流量相似。茶碱的跨毛细血管交换可能是载体介导的，其快速性导致了静脉注射该药物后不良反应的发生频率。
