Shand D G, Kornhauser D M, Wilkinson G R
J Pharmacol Exp Ther. 1975 Dec;195(3):424-32.
The effects of route of administration and blood flow on the elimination of lidocaine, diphenylhydantoin and propranolol have been investigated in the isolated perfused rat liver. After administration directly into the portal vein, drug concentrations in the reservoir were the same at a given flow rate as concentrations in the hepatic vein after drug was placed directly into the reservoir. The apparent clearance of the drug calculated from these concentrations gave an estimate of intrinsic drug clearance, which is an estimate of the activity of the drug-metabolizing enzymes. Intrinsic clearance is defined as drug clearance when flow is not rate limiting and therefore should be independent of flow. This was confirmed by showing that, at steady state, neither hepatic venous drug concentrations nor concentrations in the reservoir after portal venous administration of lidocaine were affected by altering hepatic blood flow from 10 to 20 ml/min. Propranolol was given as a single dose into the reservoir at flows of 10 and 20 ml/min. The area under the concentration-time curve (AUC) in the reservoir was decreased by increased flow, but AUC for hepatic venous blood was unchanged. Although AUC in hepatic venous blood was unchanged. Although AUC in hepatic venous blood was unchanged, higher peak concentrations and a more rapid half-life was seen in keeping with the clearance of drug from the reservoir. These data suggest that after oral drug administration, steady-state concentrations or AUC in systemic blood is dependent only on the activity of the enzymes involved (i.e., intrinsic clearance) and unaffected by flow, provided drug is completely absorbed and eliminated only by the liver. Furthermore, this will apply even to drugs whose systemic clearance and drug half-life after i.v. administration is profoundly affected by altered hepatic blood flow.
在离体灌注大鼠肝脏中，研究了给药途径和血流对利多卡因、苯妥英和普萘洛尔消除的影响。直接注入门静脉后，在给定流速下，储液器中的药物浓度与将药物直接放入储液器后肝静脉中的浓度相同。根据这些浓度计算出的药物表观清除率给出了内在药物清除率的估计值，这是对药物代谢酶活性的估计。内在清除率定义为流量不限制速率时的药物清除率，因此应与流量无关。这一点通过以下实验得到证实：在稳态下，将利多卡因经门静脉给药后，改变肝血流量从10毫升/分钟至20毫升/分钟，肝静脉药物浓度和储液器中的浓度均未受到影响。在流速为10和20毫升/分钟时，将普萘洛尔单剂量注入储液器。储液器中浓度-时间曲线下面积（AUC）随流速增加而降低，但肝静脉血的AUC未改变。尽管肝静脉血中的AUC未改变，但观察到更高的峰值浓度和更快的半衰期，这与药物从储液器中的清除情况一致。这些数据表明，口服给药后，只要药物完全吸收且仅由肝脏消除，全身血液中的稳态浓度或AUC仅取决于所涉及酶的活性（即内在清除率），不受血流影响。此外，这甚至适用于静脉注射给药后全身清除率和药物半衰期受肝血流量改变影响很大的药物。
