Hepatic Blood Flow Rate Research Articles

Hepatic and renal metabolism before and after portasystemic shunts in patients with cirrhosis.

Hepatic cirrhosis with portal hypertension and gastroesophageal hemorrhage is a disease complex that continues to be treated by surgical portasystemic shunts. Whether or not a reduction or diversion of portal blood flow to the liver adversely affects the ability of the liver to maintain fuel homeostasis via gluconeogenesis, glycogenolysis, and ketogenesis is unknown. 11 patients with biopsy-proven severe hepatic cirrhosis were studied before and after distal splenorenal or mesocaval shunts. Hepatic, portal, and renal blood flow rates and glucose, lactate, pyruvate, glycerol, amino acids, ketone bodies, free fatty acids, and triglyceride arteriovenous concentration differences were determined to calculate net precursor-product exchange rates across the liver, gut, and kidney. The study showed that hepatic contribution of glucose and ketone bodies and the caloric equivalents of these fuels delivered to the blood was not adversely affected by either a distal splenorenal or mesocaval shunt. In addition to these general observations, isolated findings emerged. Mesocaval shunts reversed portal venous blood and functionally converted this venous avenue into hepatic venous blood. The ability of the kidney to make a substantial net contribution of ketone bodies to the blood was also observed.

Role of gastrointestinal tract and liver in acetate metabolism in rat and man.

Net acetate uptake/release by various tissues was studied in vivo in fed, starved and Paromomycin-treated rats and in patients with cirrhosis of the liver. In humans the portal vein, hepatic vein and hepatic arterial blood flow rates were determined simultaneously. In rats acetate is only intestinally produced and released into the portal vein. Intestinal production is decreased by 33% in starved and Paromomycin-treated rats compared to fed animals. Portal vein hepatic vein acetate differences are linearly related to the portal vein acetate concentration (r = 0.92). Acetate uptake from the portal vein by the liver was found when the portal venous concentration exceeded 180 mumol l-1. In humans the hepatic net acetate uptake from the portal vein/net acetate release into the hepatic vein, measured as mmol min-1, is linearly related to the portal vein acetate concentration (r = 0.96). The data indicate that the liver may homeostatically regulate the systemic acetate concentration in rat and man.

Hepatic blood flow in rats with portal branch ligation.

Hepatic arterial blood flow (HABF) in the liver lobes and splanchnic nonhepatic arterial blood flow were measured in rats with and without right portal branch ligation for 1 month using 57Co microspheres. Portal branch ligation led to 60% atrophy of the ligated lobe and to hypertrophy of the nonligated lobe. In nonligated lobes of the portal branch ligation model and in the lobes of controls, HABF expressed per gram liver was comparable. In both models splanchnic non-HABF was also comparable. In the atrophic lobe, HABF remained constant; expressed per gram liver, it increased. In this lobe the net result was a significant decrease in total hepatic blood flow (ml/min/g liver).

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 V max and K m 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 μmol/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, K m and V max were calculated from both models at both low and high blood flow rates. The K m calculated according to the venous equilibration model was significantly lower in the low-flow than in the high-flow periods (P < 0.05); this model is thus not consistent with data. V max values were not influenced by hepatic blood flow. The K m calculated according to the sinusoidal perfusion model were not influenced by flow (P < 0.5) and V max was also unchanged. The sinusoidal perfusion model is thus not inconsistent with data.

Extrahepatic sulfation and glucuronidation in the rat in vivo: Determination of the hepatic extraction ratio of harmol and the extrahepatic contribution to harmol conjugation

The phenolic compound, harmol, is metabolized by sulfation and glucuronidation in the rat in vivo. In the present study, various harmol infusion rates into the jugular vein were used to delineate first-order conditions whereby total body clearance was maximal and constant; at low infusion rates the steady state harmol concentration in blood varied proportionally with the infusion rate. At infusion rates of 167 nmole/min and below, the steady state clearance of harmol was 60 ml/min or 200 ml/min/kg. Because this value for total body clearance greatly exceeded the value for hepatic blood flow rate (20 ml/min for a 300 g rat), considerable extrahepatic conjugation of harmol was suggested. At higher harmol infusion rates the total clearance decreased. Since an intraportal infusion of 167 nmole/min to the rat yielded, during steady state, the same arterial harmol blood concentration as a 52 nmole/min jugular infusion, the hepatic extraction ratio of harmol in vivo was 0.7. Extrahepatic clearance, therefore, constituted about 77% of total body clearance (after taking the difference between total body clearance and hepatic clearance). Total sulfation clearance was 52 ml/min, and greatly exceed the value for hepatic clearance (14 ml/min). Extrahepatic clearance for sulfation (at least 38 ml/min) therefore accounted for a major proportion of the sulfation activity. Blood platelets did not seem to contribute to sulfation or glucuronidation in vivo.

Absorption kinetics of some carbohydrates in conscious pigs. 2. Quantitative aspects.

Concentrations of reducing sugars, glucose, fructose and lactic acid in blood obtained from arterial and portal catheters were measured together with the portal hepatic blood flow-rate for periods of 8-24 h in twenty-six unanaesthetized pigs (mean body-weight 51 kg). The animals received experimental meals containing different amounts (100-1600 g) of different sugars (glucose fifteen meals, sucrose twenty-four meals, lactose fourteen meals, maize starch nineteen meals) together with a protein-mineral-vitamin mixture (150 g) 6-8 after implantation of the catheters and an electromagnetic flow probe. Because the portal blood flow pattern did not differ between test meals, net absorption followed the same trends as for porto-arterial concentration differences (R erat et al. 1984). Apart from lactose, the amounts of reducing sugars appearing in the portal vein correlated with the intake of the test meal, but the absorption pattern was different for each sugar. The appearance of reducing sugars was faster and earlier after intake of glucose than after sucrose and the same was the case for sucrose relative to maize starch. The differences between the three carbohydrates tended to increase with the level of intake. With a test meal containing 1 kg carbohydrate, i.e. a normal meal in a 50 kg pig, digestion of sucrose and maize starch was not finished 8 h after the meal since only 60 and 52% respectively of their hydrolysis products were recovered in the portal blood. In the case of lactose, the amounts of reducing sugars appearing in the portal blood were always very small and constant (113-118 g within 8 h) whatever the level of intake, i.e. 30 and 15% of their hydrolysis products for intakes of 400 and 800 g respectively. Depending on the carbohydrate ingested, the uptake of glucose by the gut cell wall ranged from 14 to 21 g/h and the production of lactic acid from 2.5 to 3.5 g/h.

Physiological pharmacokinetic model for distribution and elimination of pentazocine. II. Study in rabbits and scale-up to man

A physiologically based pharmacokinetic model was applied to describe the distribution and elimination of pentazocine in rabbits. For the elimination of pentazocine, the model consisted of renal, hepatic (metabolic and biliary), and GI secretion and Gl re-absorption. The tissue-to-blood partition coefficients of pentazocine in the rabbit were almost the same with those in the rat. No significant variation in hepatic blood flow rate dependent on the arterial blood concentration of pentazocine was observed in the rabbit, the results being very different from those in the rat. The time course of blood concentration after intravenous injection was proportional to dose in the range of 0.5–10 mg/kg. Excellent agreements were obtained between the predicted and observed concentrations of pentazocine after intravenous administration in the rabbit. Application of the rabbit model to prediction in man by considering the differences in organ volume, organ blood flow and renal pentazocine clearance was successful, and the model was adopted to decide the therapeutic dose of pentazocine during surgery of patients.

Physiological pharmacokinetic model for pentazocine. I. Tissue distribution and elimination in the rat

A physiologically based pharmacokinetic model was developed to describe the tissue distribution and elimination of pentazocine in the anesthetized rat. The model incorporates renal and hepatic (metabolic and biliary) elimination, GI secretion, GI reabsorption and tissue-to-blood partition coefficients. The dependency of hepatic blood flow rate on the arterial blood concentration of pentazocine is also included in the model. Excellent agreement was obtained between the predicted and observed concentrations of pentazocine in tissues and in arterial blood after a 2 mg/kg intravenous dose. Non-linear dose-dependent blood concentration-time profiles after intravenous injection of 0.5–10.0 mg/kg were successfully interpreted with the present model.

THE USE OF A MODIFIED BROMOSULPHTHALEIN EXCRETION TEST FOR THE MEASUREMENT OF HEPATIC BLOOD FLOW IN CALVES

Single intravenous injections of bromosulphthalein (BSP) were given to calves before and at intervals after the oral administration of 1000 metacercariae of Fasciola hepatica. The change in BSP concentration with time was analysed by computer to obtain the proportion of BSP extracted from plasma by hepatic cells (E) and the rate of hepatic blood flow (F). The increasing age of the normal calves during the 34 weeks of experiment had no significant effect on E or F. There was no significant effect of the duration of the fasciola lesion on E or F. When all tests on infected calves were compared as a group with tests on uninfected calves, there was a significant reduction in E(P less than 0.05) and in F(P less than 0.001) in the calves infected with F. hepatica. A survey of previously reported results suggests that sheep and cattle have a wide range of F values and that F is probably lower in 3-month-old calves than in adult cattle.

Effect of propranolol on hepatic blood flow in normal and portal hypertensive rats.

1. The effects of propranolol on heart rate, arterial pressure, portal venous pressure and fractional hepatic blood flow were studied in rats with hepatic artery ligature or with portal vein stenosis, and in sham-operated rats. The effect of propranolol on cardiac output was also studied in normal rats. 2. In rats with hepatic artery ligature or with portal vein stenosis, and in sham-operated rats, propranolol decreased heart rate and portal venous pressure significantly and did not alter arterial pressure. Propranolol decreased fractional hepatic blood flow significantly in rats with hepatic artery ligature, but did not change hepatic blood flow in rats with portal vein stenosis or in sham-operated rats. 3. We conclude therefore that: (a) propranolol decreases portal venous pressure in rats; (b) this decrease in portal venous pressure results in a reduction in portal blood flow which is related, in part, to a reduction in cardiac output; (c) propranolol does not alter hepatic blood flow in normal rats or in rats with portal hypertension.

Hepatic, gut, and renal substrate flux rates in patients with hepatic cirrhosis.

The roles of liver, kidney, and gut in maintaining fuel homeostasis were studied in 28 patients with severe hepatic cirrhosis, 25 of whom had alcohol-induced cirrhosis. Hepatic, portal, and renal blood flow rates were measured and combined with substrate concentration differences across liver, gut, and kidney to calculate the net flux of free fatty acids, ketone bodies, triglycerides, and glucose with selected glucose precursors, including glycerol, lactate, pyruvate, and amino acids. Data from the catheterization studies were related to hepatic histology, glycogen content, and activities of gluconeogenic enzymes and compared with data obtained from control patients. The effects of food deprivation on net flux of fuels across the liver, gut, and kidney were assessed after overnight and after 3d of fasting. Activities of gluconeogenic enzymes were normal, but hepatic glycogen content was diminished in cirrhotic livers, probably as a consequence of extensive hepatic fibrosis. Extrahepatic splanchnic tissues (gut) had only a small influence on total splanchnic flux rates of carbohydrates, lipids and, amino acids. In cirrhotic patients, there was no mean renal glucose contribution to the bloodstream after an overnight or after a 3-d fast. After an overnight fast hepatic glucose production in patients with cirrhosis was diminished as a result of low-rate glycogenolysis. Hepatic gluconeogenesis and ketogenesis were increased. This pattern of hepatic metabolism mimics that seen in "normal" patients after more advanced stages of starvation. After 3 d of starvation, patients with hepatic cirrhosis have hepatic gluconeogenic and ketogenic profiles comparable to those of normal patients undergoing starvation of similar duration. Nevertheless, the total number of caloric equivalents derived from ketone bodies plus glucose corrected for recycled lactate and pyruvate added to the bloodstream by the cirrhotic livers that could be terminally oxidized by peripheral tissues was less than the contributions made by the normal livers, both after and overnight and after a 3-d fast.

A new principle for estimating hepatic blood flow rates.

A new principle for estimating hepatic blood flow rates is demonstrated in steady-state experiments in rats in which p-aminohippurate, labeled with either 14C or 3H, was infused into the portal vein, with simultaneous infusion into the tail vein of the same compound labeled with the other isotope. Hepatic blood flow and hepatic extraction ratios were calculated from measurements of urinary and biliary excretion rates and blood concentrations of each isotope. The principle may be used to calculate hepatic blood flow from measurements of urinary excretion and systemic blood concentrations of drug and metabolite after intravenous injections of radiolabeled drug and precursor.

A method of determining intrinsic hepatic clearance from the first-pass effect.

1. The relation between systemic hepatic clearance, intrinsic hepatic clearance and hepatic blood fow is considered from the point of view of the sinusoidal perfusion (parallel tube) model of the liver. 2. It is shown how intrinsic hepatic clearance may be calculated, for substrates eliminated in the liver and the kidney only, from data obtained by introducing successively an oral and an intravenous dose (i.e., by using the first-pass effect) with the clinically cumbersome catheterization of the liver vein. 3. The rate of hepatic blood flow is shown to follow from the same data.

Hepatic vein oxygenation, liver blood flow, and the rate of ethanol metabolism in recently abstinent alcoholic patients.

To determine whether hepatic hypoxia is associated with hepatocellular necrosis in alcoholics, oxygen tension in the hepatic vein and hepatic blood flow were determined in thirteen patients without overt clinical liver disease. Ethanol metabolic rate was also assayed as an index of liver metabolism. Hepatic blood flow and ethanol metabolic rate were also determined in six normal volunteers. According to liver histology patients were separated into two groups, with and without hepatocellular necrosis. Alcoholics with necrosis showed a higher (P less than 0.002) ethanol metabolic rate (4.05 +/- 0.23 mmol/kg/h) than those without necrosis (2.46 +/- 0.34). Hepatic blood flow in the total group of alcoholics was not significantly different from controls; in the group with necrosis it was lower (651.7 +/- 44.6 ml/min/m2) than in the group without necrosis (878.3 +/- 81.6; P less than 0.025). Hepatic vein pO2 was lower (P less than 0.01) in patients with hepatocellular necrosis (31.7 +/- 0.68 mmHg) than in patients without necrosis (35.7 +/- 0.99). In the whole group, a significant negative correlation (r = 0.76, P less than 0.003) was observed between hepatic vein pO2 and ethanol metabolic rate. Acute administration of ethanol (21.7 mmol/kg) did not alter hepatic blood flow in six normal individuals nor in five alcoholic patients, although an increase in hepatic vein pO2 was observed in the latter. The changes observed in hepatic vein pO2 functional hepatic blood flow, and ethanol metabolic rate which correlate with hepatocellular necrosis, may be of pathogenic importance in alcoholic liver disease.

Hepatic Extraction of Long- and Short-Acting Narcotics in the Isolated Perfused Rabbit Liver

Hepatic extraction of the long-acting narcotic, methadone, was compared to that of the short-acting narcotics, morphine, diacetylmorphine, and meperidine, using an isolated perfused rabbit liver preparation. Methadone was avidly extracted from portal venous blood (86.1 +/- 0.81%) in a single pass through the liver after a bolus injection (1.5 mg) into a nonrecirculating perfusion system. Hepatic extraction of methadone was independent of rate of hepatic blood flow (0.59 to 1.53 ml per g of liver per min) but was altered by increasing the total amount of methadone injected. After a bolus injection of 15.0 and 75.0 mg, the proportions of methadone extracted were reduced to 75 and 56%, respectively. The hepatic extraction of morphine (1.5 mg) was 25%, of diacetylmorphine (1.5 mg) 59%, and of meperidine (1.5 mg) 66% in a single pass, all significantly lower (P less than 0.01) than that of methadone. Subcellular fractionation of whole liver homogenates after a single pass of drug showed that methadone and its metabolites were localized primarily in the fractions containing nuclei, mitochondria, microsomes, and other membranes, whereas morphine was primarily localized in the supernatant cytosol. Unchanged methadone was shown to be slowly released from the liver into hepatic effluent blood along with small amounts of the inactive pyrrolidine and pyrroline metabolites (identified by gas chromatography and mass spectrometry). These findings suggest that the liver may serve not only as a site of biotransformation of methadone, but also as a major reservoir for storage and subsequent release of unchanged compound.

Effect of phenformin on hepatic balances of gluconeogenic substrates in man.

The effect of a five day pretreatment with phenformin (3 X 50 mg daily) on hepatic metabolism was studied in six healthy volunteers. Arterial and hepatic venous concentrations of substrates and hepatic blood flow were estimated during a basal period and during a low-dose lactate infusion (0,03 mmol . kg-1 . min-1). The results have been compared with those obtained from untreated normal subjects in a previous study (16). During the baseline period arterial concentration of alanine and the hepatic venous concentration ratios of alanine: pyruvate and beta-hydroxybutyrate: acetoacetate were significantly increased with phenformin treatment, while the balances of carbon dioxide and glucose and the fractional extraction of alanine were decreased compared to the values obtained in untreated subjects. During lactate infusion mean arterial lactate concentration was significantly increased and hepatic lactate extraction was decreased compared to untreated persons under the same conditions. In the phenformin-treated group lactate infusion resulted in hepatic output of pyruvate and the hepatic glucose balance remained unchanged compared to baseline. Since the rate of hepatic blood flow was not increased during lactate infusion a significantly smaller glucose output and lactate uptake was obtained with phenformin. These findings support the present view that the hypoglycaemic effect of biguanides is due, at least in part, to inhibition of hepatic gluconeogenesis.

Hepatic clearance of drugs. II. Experimental evidence for acceptance of the "well-stirred" model over the "parallel tube" model using lidocaine in the perfused rat liver in situ preparation.

Theoretical analysis of two models of hepatic drug clearance revealed that one powerful discriminator between them is the effect of changes of hepatic blood flow on either the emergent drug concentration or the availability of a highly extracted compound when operating under linear conditions. Lidocaine (extraction ratio 0.997) was employed in the discriminatory studies. The behavior of this drug under linear conditions (input lidocaine concentrations < 5 mg/ liter) to changes in hepatic blood flow rate (10–16 ml/min per liver) was examined in the perfused rat liver in situpreparation. The steady-state output lidocaine concentration in the blood leaving the liver was predicted better by a “well-stirred” model than by a “parallel tube” model. As anticipated, the clearance of a poorly extracted compound, antipyrine (extraction ratio 0.08),was unaltered by changes in hepatic blood flow. These experimental findings, and the data from the literature, point to the acceptance of the “well-stirred” model, which describes the liver as a well-stirred compartment with the drug in the hepatic venous blood being in equilibrium with that in the liver.

Hepatic clearance of drugs. III. Additional experimental evidence supporting the "well-stirred" model, using metabolite (MEGX) generated from lidocaine under varying hepatic blood flow rates and linear conditions in the perfused rat liver in situ preparation.

The disposition of monoethylglycine xylidide (MEGX), a metabolite of lidocaine, was studied in the perfused rat liver in situpreparation in an attempt to further discriminate between two models of hepatic drug clearance. In the “well-stirred” model, the liver is regarded as a well-stirred compartment with the emergent drug concentration in equilibrium with that in the liver. In the “parallel tube” model, the liver is viewed as a series of indentical paralllel units with enzymes distributed evenly around the units. Using a single-passage perfusate system, we found in a previous study that the extraction ratio of lidocaine was maximal and constant (0.997) below 7 mg/liter. The steady-state output MEGX concentration appearing in the emergent blood upon a constant and low-input concentration of lidocaine (4 mg/liter) was determined under varying hepatic blood flow rates (10–16 ml/min per liver). The data suggest that operationally the “well-stirred” model adequately describes the appearance of MEGX from lidocaine.

The effect of xylazine upon hepatic glucose production and blood flow rate in the lactating dairy cow.

The effect of xylazine (Rompun) upon hepatic glucose production and blood flow rate was measured in two cows. Doses of 0-16 or 0-18 mg/kg bodyweight increased blood glucose concentrations by 200 per cent and hepatic glucose production by 400 per cent. Maximum blood glucose concentrations were reached approximately 40 minutes after dosing and did not start to fall until 185 minutes. Concentrations were near normal 24 hours after dosing. The increase in hepatic glucose production was greatest 20 minutes after dosing and production had returned to control rates 150 minutes after dosing. Visceral glucose utilisation was also increased. Blood flow rates in the hepatic and portal veins were reduced to 50 to 60 per cent of their predosing values. It is concluded that the prolonged hyperglycaemia which persists beyond 150 minutes is produced either by continued glucose production from sites other than liver and viscera or by reduced utilisation of the blood glucose by peripheral tissue.

Perfusion-limited effects of plasma drug binding on hepatic drug extraction

The hepatic elimination of phenytoin has been studied in the isolated rat liver perfused at constant flow with Krebs solution alone and in the presence of albumin. At an albumin concentration of 0.5 g/dl, 46.6% of the phenytoin was bound in the perfusate and the comparable value at 5.0 g/dl was 87.4%. The increase in binding resulted in a reduction in the hepatic extraction ratio from 0.67 in Krebs to 0.54 and 0.28 at the two albumin concentrations, respectively. Analysis of this data together with that from the literature on propranolol and warfarin indicated that they were consistent with the perfusion-limited model of hepatic clearance. Accordingly, the general relationship between the extraction ratio and the free fraction of drug in the blood is hyperbolic with the precise shape being determined by the ratio of the clearance of the drug from liver water to the hepatic blood flow rate.