Effects of perfusate flow rate on measured blood volume, disse space, intracellular water space, and drug extraction in the perfused rat liver preparation: characterization by the multiple indicator dilution technique.
Effects of perfusate flow rate on measured blood volume, disse space, intracellular water space, and drug extraction in the perfused rat liver preparation: characterization by the multiple indicator dilution technique.
复制标题
灌注液流速对灌注大鼠肝脏制剂中测量的血容量、血管空间、细胞内水空间和药物提取的影响：通过多指示剂稀释技术进行表征。
DOI：
10.1007/bf01062014
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发表时间：
1988
期刊：
影响因子：
--
通讯作者：
Goresky,CA
中科院分区：
文献类型：
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作者：
Pang,KS;Lee,WF;Cherry,WF;Yuen,V;Accaputo,J;Fayz,S;Schwab,AJ;Goresky,CA
在一次性灌注大鼠肝脏制剂中研究了肝血流对消除几种高度透明底物的影响。将恒定且低输入浓度的乙醇 (2.0 mM)、[14C]-非那西丁和 [3H]-对乙酰氨基酚 (分别为 0.36 和 0.14 μM) 或哌替啶 (8.1 μM) 在五个流动周期（每个 > 35 分钟）中一次性输送到大鼠肝脏制备物中； 12 毫升/分钟的控制流量周期因流量更改为 8 或 16 毫升/分钟而中断。 12 ml/min 时的稳态肝脏利用率（F 或流出存活率）为乙醇，0.075±0.038； [14C]-非那西丁，0.15±0.059； [3H]-对乙酰氨基酚，0.34±0.051；哌替啶，0.047±0.017。不同化合物之间的流量引起的变化是不同的：随着流量减少（8 ml/min），乙醇（0.061 ±0.032）和[3H]-对乙酰氨基酚（0.28±0.051）的F降低，如预期，但[14C]-非那西丁（0.20 ±0.068）和哌替啶（0.05 ±0.03）增加；随着流量增加（至 16 ml/min），所有化合物的 F 均增加，正如预期的较短停留时间：乙醇，0.13 ±0.065； [14C]-非那西丁，0.22±0.062； [3H]-对乙酰氨基酚，0.43±0.063；哌替啶，0.055±0.022。由于非线性代谢，当流量从 12 毫升/分钟变为 16 毫升/分钟时，乙醇的 F 显着增加；后者通过浓度增加（1.8 至 11.4mM）时提取率降低得到证实；其他化合物不存在这种情况。为了解释观察结果，我们使用多指示剂稀释技术来研究灌注大鼠肝脏制剂中血管和细胞内参考的组织分布空间的流动诱导行为。将非消除参考物质[51Cr标记的红细胞（血管标记物）、125I标记的白蛋白、[14C]-蔗糖（细胞外标记物）和[3H]-H2O（细胞标记物）]快速注射到以随机选择的流速（5、8、10、12、14或16ml/min）灌注的肝脏门静脉中，肝静脉对流出曲线进行了表征。估计的血窦血容量、总白蛋白和蔗糖分布空间、Disse空间、总水空间和细胞内水的通过时间与血流速率有很强的相关性。然而，没有发现血液/水流速和细胞内水空间（基质也进入的空间）之间的相关性。在 < 0.75 ml 血液/min/g 肝脏时，细胞内水空间减少，但在 > 0.75 ml 血液/min/g 肝脏时，观察到的值是恒定的（0.635±0.024 ml/g 肝脏）并且与流速无关。对细胞水平均通过时间的估计可以计算封存速率常数（每毫升细胞水的固有清除率）。当流量从 12 ml/min 降低至 8 ml/min 时，哌替啶和非那西丁的估计螯合速率常数降至 64%，而对乙酰氨基酚（由非那西丁预先形成或生成）的估计螯合速率常数则降至最低（10% 至 11%），并且当流量从 12 ml/min 变为 16 ml/min 时，大多数化合物的螯合速率常数通常保持不变。综合研究结果表明，需要临界流量来维持肝细胞的最大且持续的可及性。正如药物代谢数据所表明的，低于该临界值的流速对肝细胞募集的影响不同。在临界流速以下，细胞内空间的减少主要影响由位于肝周围小静脉区域的酶介导的药物的代谢加工，但对于涉及门静脉周围区域的酶系统的药物的生物转化，这种影响实际上是不可察觉的。
The effect of hepatic blood flow on the elimination of several highly cleared substrates was studied in the once-through perfused rat liver preparation. A constant and low input concentration of ethanol (2.0 mM), [14C]-phenacetin and [3H]-acetaminophen (0.36 and 0.14 μM, respectively), or meperidine (8.1 μM) was delivered once-through the rat liver preparation in five flow periods (>35 min each); control flow periods at 12 ml/min were interrupted by flow changes to 8 or 16 ml/min. The steady-state hepatic availabilities (F or outflow survivals) at 12 ml/min were ethanol, 0.075±0.038; [14C]-phenacetin, 0.15±0.059; [3H]-acetaminophen, 0.34±0.051; meperidine, 0.047±0.017. Flow-induced changes were different among the compounds: with reduced flow (8 ml/min), F was decreased for ethanol (0.061 ±0.032) and [3H]-acetaminophen (0.28±0.051), as expected, but was increased for [14C]-phenacetin (0.20 ±0.068) and meperidine (0.05 ±0.03); with an elevation of flow (to 16 ml/min), F was increased for all compounds, as expected of shorter sojourn times: ethanol, 0.13 ±0.065; [14C]-phenacetin, 0.22 ±0.062; [3H]-acetaminophen, 0.43 ±0.063; meperidine, 0.055±0.022. A marked increase in F for ethanol had occurred when flow changed from 12 to 16 ml/min due to nonlinear metabolism; the latter was confirmed by a reduction in the extraction ratios at increasing concentrations (1.8 to 11.4mM); this condition was not present for the other compounds. In order to explain the observations, we used the multiple indicator dilution technique to investigate the flow-induced behaviors of tissue distribution spaces of vascular and intracellular references in the perfused rat liver preparation. After a rapid injection of noneliminated reference materials [51Cr-labeled RBC (vascular marker),125I-labeled albumin, [14C]-sucrose (extracellular markers), and [3H]-H2O (cellular marker)] into the portal veins of livers perfused at the randomly chosen flow rates (5, 8, 10, 12, 14, or 16 ml/min), the hepatic venous outflow profiles were characterized. Estimated sinusoidal blood volume, total albumin and sucrose distribution spaces, the Disse space, total water space, and the transit time for intracellular water showed strong correlations with blood flow rate. No correlation was found, however, between blood/water flow rate and intracellular water space (a space also accessed by substrates). At < 0.75 ml blood/min/g liver, intracellular water space was decreased, but at > 0.75 ml blood/min/g liver, the observed values were constant (0.635±0.024 ml/g liver) and independent of flow rate. Estimations of the mean transit time for cell water enabled calculations of sequestration rate constants (intrinsic clearance per ml cell water). The estimated sequestration rate constants for meperidine and phenacetin were decreased to 64% when flow was decreased from 12 to 8 ml/min, whereas those for acetaminophen (preformed or generated from phenacetin) were decreased minimally (10 to 11%), and these were generally unchanged for most compounds when flow was altered from 12 to 16 ml/min. The composite findings suggest that a critical flow is required to maintain maximal and constant accessibility into hepatocytes. Flow rates below this critical value affect hepatocyte recruitment differentially, as suggested by drug metabolic data. Below the critical flow rate, the reduction in intracellular space affected mostly metabolic processing of drugs that are mediated by enzymes located in the perihepatic venular region, but the effects are virtually imperceptible for biotransformation of drugs that involve enzyme systems in the periportal region.