Krejcie T C, Wang Z, Avram M J
Northwestern University Medical School, Department of Anesthesiology, Chicago, Illinois, USA.
J Pharmacol Exp Ther. 2001 Mar;296(3):922-30.
Recirculatory pharmacokinetic models for indocyanine green (ICG), inulin, and antipyrine facilitate description of intravascular mixing and tissue distribution following intravenous administration. These models characterized physiologic marker disposition in four awake dogs under control conditions and during phenylephrine, isoproterenol, and nitroprusside infusions. Systemic vascular resistance was more than doubled by phenylephrine and was decreased more than 50% by both isoproterenol and nitroprusside. Dye (ICG) dilution cardiac output (CO) was decreased nearly one-third by phenylephrine, was more than doubled by isoproterenol, and was largely unaffected by nitroprusside. Although phenylephrine reduced CO, the fraction of CO represented by nondistributive blood flow nearly doubled at the expense of blood flow to rapidly equilibrating tissues. The area under the blood antipyrine concentration versus time relationship for 3 min after administration (AUC(0-3 min)) during the phenylephrine infusion was nearly 75% larger than control due to both increased first-pass AUC and an increased fraction of CO represented by nondistributive blood flow. The large increase in CO produced by isoproterenol increased blood flow to rapidly equilibrating tissues and relatively decreased blood flow to slowly equilibrating tissues, because some appeared to equilibrate rapidly. Antipyrine AUC(0-3 min) during the isoproterenol infusion decreased more than 30%, due to decreased first-pass AUC. Nitroprusside changed antipyrine intercompartmental clearances in proportion to CO and, hence, had little effect on antipyrine AUC(0-3 min). These data provide further evidence that changes in antipyrine (a lipophilic drug surrogate) blood flow-dependent distribution after rapid i.v. administration are not proportional to changes in CO but depend on both CO and its distribution.
用于吲哚菁绿（ICG）、菊粉和安替比林的再循环药代动力学模型有助于描述静脉给药后血管内混合和组织分布情况。这些模型对四只清醒犬在对照条件下以及去氧肾上腺素、异丙肾上腺素和硝普钠输注期间的生理标志物处置情况进行了表征。去氧肾上腺素使全身血管阻力增加了一倍多，而异丙肾上腺素和硝普钠均使其降低了50%以上。染料（ICG）稀释法测得的心输出量（CO）在去氧肾上腺素作用下降低了近三分之一，在异丙肾上腺素作用下增加了一倍多，而在硝普钠作用下基本未受影响。尽管去氧肾上腺素降低了CO，但非分布性血流占CO的比例几乎增加了一倍，代价是流向快速平衡组织的血流减少。在去氧肾上腺素输注期间，给药后3分钟内血液中安替比林浓度与时间关系曲线下的面积（AUC(0 - 3 min)）比对照值大近75%，这是由于首过AUC增加以及非分布性血流占CO的比例增加所致。异丙肾上腺素引起的CO大幅增加增加了流向快速平衡组织的血流，相对减少了流向缓慢平衡组织的血流，因为有些组织似乎平衡得很快。异丙肾上腺素输注期间安替比林的AUC(0 - 3 min)降低了30%以上，原因是首过AUC降低。硝普钠按与CO成比例的方式改变了安替比林的跨房室清除率，因此对安替比林的AUC(0 - 3 min)影响很小。这些数据进一步证明，快速静脉给药后，安替比林（一种亲脂性药物替代物）血流依赖性分布的变化与CO的变化不成比例，而是取决于CO及其分布情况。
