A dispersion model of hepatic elimination: 2. Steady-state considerations-influence of hepatic blood flow,binding within blood,and hepatocellular enzyme activity

The dispersion model of hepatic elimination is based on the distribution of residence times of blood elements within the liver. The model has two asymptotic solutions corresponding to the wellstirred model (complete mixing of blood elements) and the parallel-tube model (no variation in residence times of blood elements). The steady-state form of the dispersion model relevant to pharmacokinetic analysis is developed and explored with respect to changes in blood flow, in binding within blood, and in hepatocellular enzyme activity. Literature data are used to evaluate discrepancies among the predictions of the dispersion, well-stirred, and tube models. It is concluded that the dispersion model is consistent-with the data. The limitations of steady-state perfusion experiments to estimate the residence time distribution of blood elements within the liver are considered.     

A dispersion model of hepatic elimination: 2. Steady-state considerations--influence of hepatic blood flow, binding within blood, and hepatocellular enzyme activity

The dispersion model of hepatic elimination is based on the distribution of residence times of blood elements within the liver. The model has two asymptotic solutions corresponding to the "well-stirred" model (complete mixing of blood elements) and the "parallel-tube" model (no variation in residence times of blood elements). The steady-state form of the dispersion model relevant to pharmacokinetic analysis is developed and explored with respect to changes in blood flow, in binding within blood, and in hepatocellular enzyme activity. Literature data are used to evaluate discrepancies among the predictions of the dispersion, well-stirred, and tube models. It is concluded that the dispersion model is consistent with the data. The limitations of steady-state perfusion experiments to estimate the residence time distribution of blood elements within the liver are considered.     

A comparison of the influence of famotidine and cimetidine on phenytoin elimination and hepatic blood flow.

The H2-receptor antagonist cimetidine has been reported to decrease the hepatic clearance of numerous drugs by inhibiting cytochrome P-450 metabolism, decreasing liver blood flow or both. In this open-label, randomized crossover study we determined whether therapeutic doses of famotidine, a newer H2-receptor antagonist, has similar effects. Ten healthy subjects received single doses of both phenytoin 100 mg orally and indocyanine green intravenously without other treatment, and then again during treatment with famotidine or cimetidine. After a drug-free period, this sequence was repeated with the alternate H2-receptor antagonist. Cimetidine decreased the plasma clearance of phenytoin by 16% +/- 14% (mean +/- s.d.), but was not found to have a significant influence on phenytoin volume of distribution or terminal elimination rate constant nor on blood clearance of indocyanine green. Famotidine was not found to alter either phenytoin or indocyanine green kinetics.     

半肝血流阻断在原发性肝癌肝脏部分切除术中的应用观察

目的：探讨在肝部分切除手术中应用半肝血流阻断的临床效果。方法：将67例肝脏部分切除原发性肝癌患者随机分为研究组及对照组,对照组采用常规全肝血流阻断,研究组采用切除侧半肝血流阻断,比较两组患者术中出血情况、连续阻断时间及术后肝功能情况。结果：研究组患者术中出血少于对照组,连续阻断时间长于对照组,两组患者术前AST、ALT、CHE及PA水平无显著差异,患者术后1d及7dAST、ALT水平低于对照组,CHE、PA水平高于对照组。结论：半肝血流阻断技术能够延长肝脏切除术中连续阻断时间,减少肝功能损伤。     

Variation in hepatic extraction ratio with unbound drug fraction: discrimination between models of hepatic drug elimination

Systematic examination of model-dependent predictions of changes in the hepatic extraction ratio (E), following alteration in the unbound fraction of drug in plasma (fub), should allow sensitive discrimination between the venous equilibrium model (model I) and the sinusoidal perfusion model (model II) of hepatic sinusoidal function if drugs which show high clearance of free drug are used. Analysis of experimental data from the literature confirmed the utility of this approach. Specifically, data related to diazepam (E = 0.95 at fub = 1) clearly conformed to the predictions of the sinusoidal perfusion model and differed markedly from those of the venous equilibrium model. Conversely, data for phenytoin (E = 0.69 at fub = 1) failed to discriminate between models, as predicted by our analysis. We identify a sensitive, convenient method for discrimination between current models of hepatic sinusoidal function and establish for the first time that a drug substrate (diazepam) conforms closely to the predictions of the sinusoidal perfusion model.     

The effect of theophylline on estimated hepatic blood flow

We observed the effect of aminophylline administration on estimated hepatic blood flow. Indocyanine green (ICG) 0.5 mg/kg was administered as an intravenous bolus dose before and after intravenous infusion of 7 mg/kg aminophylline. Venous blood was collected at timed intervals over 15 minutes to construct ICG concentration-time graphs. Pharmacokinetic values were calculated using non-compartmental methods. Estimated hepatic blood flow decreased from 790 +/- 190 to 665 +/- 100 ml/minute (p less than 0.05) after administration of aminophylline.     

A theoretical examination of the effects of gut wall metabolism,hepatic elimination,and enterohepatic recycling on estimates of bioavailability and of hepatic blood flow

A model including two eliminating compartments (the liver and the gastrointestinal mucosa) and a noneliminating compartment (the blood or central compartment) was developed to predict the effects of hepatic elimination, gastrointestinal mucosal metabolism, and the occurrence of enterohepatic recycling of a drug and its metabolites on the area under the blood concentrationtime curve (AUC). Several limiting cases where complete absorption or complete or nonexistent enterohepatic recycling of a drug and its metabolite occurred were only considered. Under linear kinetic conditions, the occurrence of hepatic elimination and enterohepatic recycling of a drug and its metabolite in the absence of intestinal mucosal metabolism should affect only the area under the curve and not the availability for both the intraperitoneal and the oral dose. In the presence of intestinal mucosal metabolism, the area under the curve should change with different routes of administration; a larger area, hence a higher availability, should occur after intraperitoneal administration than after oral administration of the drug. For a drug which is eliminated solely by the liver, apparent hepatic flow can be estimated by the dose divided by the difference in the area under the curve for an intravenous dose and the area under the curve for the same intraperitoneal or oral dose. In the absence of gastrointestinal mucosal metabolism, the presence of enterohepatic recycling of a drug and its metabolite should not affect the estimation of apparent hepatic blood flow. However, when gastrointestinal mucosal metabolism is present, there should be an overestimation of hepatic flow when AUC_i.p. and AUC_i.v. are used and a slight underestimation of hepatic flow when AUC_i.v. and AUC_p.o. are used.     

Hepatic blood flow and drug metabolism in patients on enzyme-inducing anticonvulsants

Summary Liver blood flow and indices of hepatic drug metabolism (antipyrine elimination rate and cytochrome P-450 concentration in liver biopsy specimens) were studied in 19 epileptics on long-term anticonvulsant treatment, and in 18 controls. The size of the liver and the total estimated liver blood flow were greater in the epileptics than in the controls, whereas the relative liver blood flow (per unit weight of the liver) was not significantly different. The epileptics had higher cytochrome P-450 levels and they eliminated antipyrine faster than the controls. It was concluded that long-term ingestion of enzyme-inducing anticonvulsants is associated with an increase in the total hepatic blood flow in parallel with the increase in liver size, and not as an independent phenomenon. Since the relative perfusion rate of the hepatocytes was unchanged, the enhanced activity of drug metabolizing enzymes is presumed to be mainly responsible for the increased drug clearance observed in epileptic subjects.     

Current models of hepatic pharmacokinetics: flow effects on kinetic constants of ethanol elimination in perfused rat liver

At present two different pharmacokinetic models of the enzymic elimination of substances from the blood flowing through the liver are used: the sinusoidal perfusion model assuming the elimination to take place at the local sinusoidal blood substrate concentration, falling continuously from the inlet to the outlet of the sinusoid, and the venous equilibration model assuming elimination at the hepatic outlet concentration. It is an ultimate requirement of such models that the estimates of the enzymic parameters Vmax and Km be independent of variations in hepatic blood flow rate. This was used to compare the two models experimentally. Ethanol was given at two successive constant infusion rates (7 and 10 mumol/min) to 11 livers from rats (200 g) perfused by a recirculating medium. In each of the infusion periods the hepatic blood flow rate was varied experimentally (10 and 17 ml/min, respectively). From the measured steady-state ethanol concentrations in the hepatic inlet and outlet, Km and Vmax were calculated from both models at both low and high blood flow rates. The Km calculated according to the venous equilibration model was significantly lower in the low-flow than in the high-flow periods (P less than 0.05); this model is thus not consistent with data. Vmax values were not influenced by hepatic blood flow. The Km calculated according to the sinusoidal perfusion model were not influenced by flow (P less than 0.5) and Vmax was also unchanged. The sinusoidal perfusion model is thus not inconsistent with data.     

Hepatic blood flow and enzyme induction in the rat

Hepatic blood flow and hepatic BSP extraction were estimated in 11 rats injected with phenobarbital for four days and in 10 controls. Hepatic blood flow was not significantly different in phenobarbital-treated rats (8.42 ± 2.43 ml/min per 100g body wt or 1.71 ± 0.42 ml/min per g liver, mean ± 1 S.D.) and in untreated rats (6.64 ± 2.76 ml/min per 100 g body wt or 2.04 ± 0.94 ml/min per g liver). In contrast, BSP extraction was significantly higher in phenobarbital-treated rats (0.83 ± 0.09) than in controls (0.69 ± 0.16; P < 0.05). These results suggest that the increase in BSP clearance observed in phenobarbital-treated rats results from increased hepatic BSP extraction and not from increased hepatic blood flow.     

Hepatic elimination of femoxetine in pig

Hepatic elimination of femoxetine was studied in seven anaesthetized 40 kg pigs by means of constant rate infusions of 3-41 mg/min. (8.6-118 mumol/min.) into the portal vein. The elimination followed saturation kinetics (Micha?lis-Menten constants: Vmax 12 mg . min.-1 . kg-1 liver; Km 1.3 mg . 1-1 blood) and was characterised by high hepatic extraction, due to metabolism. The hepatic output of the active metabolite, nor-femoxetine, was very low, indicating that other metabolic pathways than demethylation were more important in the pig. The high hepatic elimination in the pig corresponds to the high first pass effect, earlier found in man, and it depends upon the infusion rate as well as the total dose.     

Effect of ACP (pyridoxine-2-oxoglutarate) on hepatic failure after diversion of portal blood flow

The protective effect of pyridoxine-2-oxoglutarate (ACP) was studied in end-to-side porto-caval shunted rats. A significant improvement of hepatic conditions was shown in ACP-treated rats, while an increased mortality was observed in pyridoxine and 2-oxoglutarate treated rats. Serum glutamic-oxaloacetic transminase, glutamicpyruvic transaminase and lactic dehydrogenase activities, composition of serum proteins, liver mitochondria oxygen consumption rate, plasma ammonia were tested.     

Altered hepatic blood flow and drug disposition.

For some drugs, delivery to the liver by the hepatic circulation is an important determinant of removal by this organ. Classical pharmacokinetic analyses cannot predict the changes produced by altering any of the biological determinants of drug elimination by the liver; hepatic blood flow, metabolic enzyme activity, drug binding and route of administration. However, with the use of a physiological model of hepatic drug elimination, such predictions can be made. This model has been tested experimentally and appears to be valid. Hepatic blood flow can vary over about a 4-fold range from half normal flow to twice logical changes affecting the circulation. For drug clearance to be affected significantly by these changes in flow, the drug must be avidly removed by the liver as reflected in a high hepatic extraction ratio and intrinsic hepatic clearance. This latter term is a useful way to characterise the ability of the liver to irreversibly remove drug from the circulation in the absence of any flow limitation. The clearance of drugs with low intrinsic clearance will not be affected significantly by changes in liver blood flow.     

Effect of dopamine on hepatosplanchnic blood flow

Hepatosplanchnic blood flow (EHBF) was estimated with the single-injection method using indocyanine green in 10 patients without cardiac failure before and after 20 min of an intravenous infusion of dopamine. Five patients received 4 microgram/kg/min and another 5 patients 8 microgram/kg/min. The cardiac index (CI) was determined according to the Fick principle, and the arterio-hepatovenous oxygen difference (AV DO2 AO/HV) was measured. The mean increase in EHBF in the 10 patients was from 640 +/- 46 ml/min/m2 to 831 +/- 56 ml/min/m2 (p less than 0.001). The percentage of EHBF to CI increased from 24.1 +/- 2.0% to 26.4 +/- 1.6% (p less than 0.05). The mean AV DO2 AO/HV dropped from 49.6 +/- 3.8 ml/liter to 40.4+/- 2.9 ml/liter (p less than 0.005). We conclude that dopamine given at rates of 4 and 8 microgram/kg/min to patients whose hearts are well compensated increases hepatosplanchnic flow. Thus, the large increase in renal blood flow which occurs with dopamine is not at the expense of hepatosplanchnic blood flow.