Increase In Liver Blood Flow Research Articles

Clinical pharmacokinetics and endocrine disorders. Therapeutic implications.

Endocrine disorders are common and produce widespread changes in cellular and organ function. Alterations in the sensitivity of patients with thyroid disorders to digoxin, anticoagulants and sedatives have been recognised for many years. Many of the recently documented kinetic alterations in endocrine patients are explicable on the basis of disease-induced changes in hepatic drug metabolism, protein binding and renal function. In hyperthyroidism the rate of absorption of paracetamol, propranolol and oxazepam is increased due to increased gastrointestinal motility. The volume of distribution of propranolol and digoxin is increased and there is decreased binding of both basic and acidic drugs as a consequence of alterations in alpha 1-acid glycoprotein and albumin concentration. The rate of glucuronidation of paracetamol and oxazepam is increased in hyperthyroidism. While oxidative metabolism of antipyrine, propranolol, metoprolol and theophylline is enhanced, the clearance of a number of other agents, including diazepam, warfarin, antithyroid drugs and phenytoin, is unaltered. The systemic clearance of propranolol is enhanced as a consequence of a 50% increase in liver blood flow. The rate of elimination of a number of endogenous substances, including cortisol, thyroid hormones and insulin, also appear to be enhanced. Hyperthyroidism has a variable effect on renal function, with a possible increase in digoxin elimination, but no effect on the clearance of renally excreted beta-blockers, atenolol, sotalol and nadolol. These kinetic changes suggest that individualization and higher than normal dosage of propranolol is necessary to control hyperthyroidism, and in thyrotoxic atrial fibrillation higher doses of digoxin or additional therapy with beta-blockers, or verapamil, may be indicated. The increased sensitivity of thyrotoxic patients to warfarin suggest care with dosage and frequent monitoring of response are warranted. Less information is available concerning hypothyroidism, but there is a general trend for decreased absorption of paracetamol and propranolol. In addition, the volume of distribution of digoxin is reduced, as is renal clearance. Limited studies suggest no alteration in the glucuronidation of oxazepam, but antipyrine clearance appears to be reduced. Steady-state propranolol concentrations are elevated in hypothyroidism and there appears to be a decreased metabolism of thyroid hormones and cortisol. Preliminary information suggests the binding of propranolol is increased. Thus, in the treatment of hypothyroid patients, a lower dosage of propranolol may be required.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of endoscopic sclerotherapy of esophageal varices on liver blood flow and liver function. An experimental study.

In 10 Göttingen mini-pigs esophageal varices developed after banding of the portal vein. In five pigs the varices were treated by paravariceal injection of polidocanol, and the rest served as controls. As judged from endoscopy and portography, the varices disappeared after four sclerotherapy sessions within 4 weeks, and at the same time portal venous pressure rose from 19 to 38 mm Hg. No changes were seen in the control group. After 24 weeks of observation the hepatic blood flow in the untreated group was 10 ml/kg/min, and portal angiography showed that nearly all the portal blood bypassed the liver. In the pigs treated with sclerotherapy the hepatic blood flow increased to 28 ml/kg/min, angiography showed a normal hepatogram, and no filling of the collaterals was seen. Sclerotherapy induced only a few changes in liver function, and these may be related to the concomitant increase in liver blood flow.

Ethanol-induced increase in portal hepatic blood flow: interference by anesthetic agents.

While a number of studies show that acute oral administration of ethanol results in increases in liver blood flow, a large body of evidence has also been presented in which such an effect is not observed. To shed light on this discrepancy, we have studied in rats, a number of variables that might modulate or inhibit the effect of ethanol. These included the use of three anesthetic agents studied at two different times after anesthetic administration and the effect of animal age, gender, batches and seasonal variation. Portal blood flows were determined by the radiolabeled microsphere method in 12 separate experiments in awake rats. Ethanol given at doses ranging from 0.5 to 4.0 gm per kg consistently increased portal vein blood flow by approximately 50% (42.2 +/- 3.5 to 63.4 +/- 6.5 ml per min per kg). The interexperiment variation was 2.4 to 3.0%, showing remarkable consistency, typical of an all-or-none effect at the doses employed. On the other hand, the ethanol-induced increase in portal blood flow was completely suppressed by ketamine (75 mg per kg), thiopental (50 mg per kg) and fentanyl (15 micrograms per kg) when given 15 min prior to blood flow determinations. This suppression was dependent on the dose and duration of anesthesia. These anesthetic agents had no effect on basal hepatic arterial or portal blood flows. Ethanol or the anesthetics were without effects on hepatic artery blood flow. Neither gender, weight (150 to 350 gm) nor animal batch had effect on the response to ethanol. Similarly, there was no effect of seasonal variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Verapamil pharmacokinetics and apparent hepatic and renal blood flow.

The effect of acute and continued administration of verapamil on pharmacokinetics and regional blood flow has been studied in eight normotensive subjects. Continued administration resulted in a significant decrease in verapamil clearance, compared to that following acute dosing, as assessed by increases in both terminal elimination half-life (from a mean +/- s.d. of 5.2 +/- 2.3 h to 6.7 +/- 2.0 h) and AUC (from a mean +/- s.d. of 800 +/- 353 ng ml-1 h to 1455 +/- 244 ng ml-1 h). The relative clearance of norverapamil was not changed. Acute administration of verapamil resulted in a significant increase (P less than 0.005) in apparent liver blood flow which with continued administration fell significantly (P less than 0.01) towards placebo values. Effective renal plasma flow similarly increased with acute verapamil administration (P less than 0.05) and with chronic administration reduced again to be not significantly different from placebo. Acute and chronic verapamil administration did not significantly alter glomerular filtration rates. These results suggest that there may be a relationship between the acute increase in liver blood flow and the relatively increased clearance of verapamil following acute dosing.

Recovery of liver function in partially hepatectomized rats evaluated by aminopyrine demethylation capacity.

Aminopyrine demethylation was investigated in rats after a 70% hepatectomy to assess possible parallelism between the recovery of mass and function. Tests were performed by analyzing 14CO2 exhalation from 0.1 microCi per 100 gm of body weight of [dimethylamine-14C]aminopyrine given intraperitoneally with incremental doses of unlabeled drug. Early after 70% hepatectomy, Vmax was reduced by 52%. This discordance between mass and function was not due to extrahepatic aminopyrine demethylation, since liver exclusion reduced demethylation of aminopyrine to nearly nil. Whether it results from increased liver blood flow in the remnant liver is less clear: portacaval anastomosis provoked an identical fall in Vmax and liver blood flow, but aortal-portal fistula which increased liver blood flow by 70% did not modify Vmax. The early increase in Vmax could be related to a "hepatotrophic" factor of splanchnic origin which increased after partial hepatectomy and decreased after portacaval shunt. After the early period, Vmax, expressed per gram of actual liver weight, returned to control range. Throughout regeneration (4 to 144 hr), no modification was observed in Km nor in cytochrome P-450 concentration. Enzymatic induction with phenobarbital increased the demethylation capacity more than liver weight in intact and regenerating liver. Except for the first hours after partial hepatectomy or after enzymatic induction, the aminopyrine demethylation capacity directly correlated with liver mass and may be useful in evaluating liver regeneration in vivo.

The effects of vasopressin on hepatic haemodynamics in the cirrhotic and non-cirrhotic rat.

Liver blood flow (xenon-133 clearance method) and portal venous flow were measured in cirrhotic and non cirrhotic rats following the infusion of vasopressin at varying rates. At low rates of infusion, vasopressin had no significant effect on portal venous flow or liver blood flow in cirrhotic or non-cirrhotic rats. Infusion of vasopressin at a rate of 0.08 microU/g body wt/min in non-cirrhotic rats and 0.04 and 0.08 microU/g body wt/min in cirrhotic rats decreased portal venous flow and increased liver blood flow. At higher rates of infusion (0.2 microU/g body wt/min in non-cirrhotic rats and 0.16 microU/g body wt/min in cirrhotic rats) these effects were reversed. Furthermore, an infusion of 0.08 microU/g body wt/min vasopressin significantly reduced portal pressure in the cirrhotic rat. However, portal pressure was not significantly altered following an infusion of 0.16 microU/g body wt vasopressin. The implications of these findings in relation to the possible deleterious effects of high rates of vasopressin infusion in the management of portal hypertension and bleeding oesophageal varices is discussed.

Nifedipine increases and glyceryl trinitrate decreases apparent liver blood flow in normal subjects.

The effects of sublingual nifedipine (10 mg) and of glyceryl trinitrate (500 micrograms), which produce arterial and venous vasodilatation respectively, on indocyanine green estimated apparent liver blood flow (LBF) were studied in six healthy volunteers. Nifedipine significantly increased (33 +/- 12%; mean +/- s.e. mean) and glyceryl trinitrate significantly reduced (18 +/- 3%) LBF. There was a positive relationship (r = 0.92, P less than 0.05) between the reduction in mean arterial pressure produced by nifedipine and the percentage increase in LBF. These results show that single doses of nifedipine and glyceryl trinitrate significantly alter LBF.

Clinical pharmacokinetics of beta-adrenoceptor blocking drugs in thyroid disease.

β-Adrenoceptor blocking drugs (β-blockers) have an established place in the management of patients with thyroid disease. Thyroid hormones, however, markedly alter hepatic, renal and cardiovascular function and thus may significantly influence drug disposition. In hyperthyroidism the clearance of propranolol following intravenous administration is increased by approximately 50%, an effect that may be attributed to the marked increase in liver blood flow that occurs in this condition. On the other hand, the increased clearance of propranolol during long term oral therapy is presumably due to increased hepatic drug metabolising enzyme activity. However, following single oral doses the clearance of propranolol has been reported both to be unchanged and increased in hyperthyroid patients. Both during single dose and long term therapy the elimination half-life of propranolol is unaltered, in part due to an increased apparent volume of distribution. The degree of plasma protein binding of propranolol appears to be slightly reduced in the hyperthyroid state.

Elimination of pindolol in liver disease.

The elimination of pindolol was studied in 32 patients suffering from various liver diseases, mainly acute hepatitis and hepatic cirrhosis. The total body clearance of antipyrine was measured simultaneously as a parameter of liver microsomal enzyme activity. The doses given were antipyrine 1000 mg orally and pindolol 3 mg i.v. Plasma samples were taken and urine was collected for up to 72 h for the measurement of drug concentrations. In addition, conventional biochemical laboratory tests were done. The total body clearance of antipyrine was compared with the pharmacokinetic parameters calculated for pindolol, and the results of the biochemical tests. No correlation was found between antipyrine clearance and the routine biochemical parameters in liver disease or with the total body clearance of pindolol. A significant correlation was seen with the nonrenal clearance of pindolol taken as representing its major metabolic degradation. Higher correlation coefficients were observed when two subgroups of patients with acute hepatitis and hepatic cirrhosis were separated. In some patients suffering from hepatic cirrhosis a higher urinary excretion of unchanged pindolol was observed as liver function become decompensated, a finding due to an unknown mechanism but based on intact renal function. In patients with acute hepatitis a much higher nonrenal clearance was found than in many other patients, which might be based on increased liver blood flow.

The effect of different doses of dimethylbiguanide (DMB) on liver blood flow, Blood glucose and plasma immunoreactive insulin in anaesthetized rats

The effect of different doses of dimethylbiguanide (DMB) administered by the i.v. and i.d. route on liver blood flow, blood glucose and plasma immunoreactive insulin was investigated in anaesthetized rats. Liver blood flow was measured by thermocouples implanted into the liver utilising Grayson's principle of “internal calorimetry”. In addition blood glucose and immunoreactive insulin in the plasma was measured at different time intervals following the different doses of DMB. Intraarterial BP was monitored during the whole experiment. Following 100 mg/kg DMB i.v. a significant increase in liver blood flow, blood glucose, plasma immunoreactive insulin and BP was observed. 50 mg/kg DMB i.v. did not affect any of the parameters measured, while 150 mg/kg DMB was already a toxic dose. After i.d. administration no changes were seen following a dose of 175 mg/kg DMB and 1500 mg/kg DMB was already toxic. 500 mg/kg, however, showed a similar significant increase in liver blood flow, blood glucose, plasma immunoreactive insulin and BP was observed. 50 mg/kg effects observed could be suppressed by a simultaneous administration of 1 mg/kg propranolol i.v. In addition a decrease in liver blood flow occurred which is explained by a direct effect of the β-adrenergic blocking agent propranolol on the liver vasculature. Therefore a selective β-adrenergic effect of the biguanides seems a likely explanation for the increased liver blood flow following DMB administration. Administering 1.6 g/kg glucose i.d. an increase in liver blood flow, blood glucose and plasma immunoreactive insulin was observed. This influence on blood glucose and plasma immunoreactive insulin was inhibited by simultaneous administration of 1.6 g/kg glucose and 500 mg/kg DMB, while liver blood flow showed the same increase when glucose alone was given. After changing the experimental design in giving the 500 mg/kg DMB i.d. and 30 min later 1.6 g/kg glucose a much higher increase in liver blood flow occurred, which might reflect an additive effect.

Influence of phenobarbital on factors responsible for hepatic clearance of indocyanine green in the rat: Relative contributions of induction and altered liver blood flow

The influence of phenobarbital, 3,4-benzpyrene and 3-methylcholanthrene on the clearance of indocyanine green (ICG) in the rat was investigated. ICG clearance following rapid i.v. administration of 1, 10 and 50 mg/kg, body wt was dose-dependent and pretreatment for 10 days with the inducing agents produced an increase in clearance only in the case of phenobarbital. All three inducers when given in this manner have been reported to produce equivalent increases in ligandin, consequently, this protein cannot be a major rate-limiting factor for hepatic ICG removal in the rat. Of the three inducing agents studied, only phenobarbital increases liver blood flow. The relative contribution of this change versus any increase in the liver's intrinsic ability to remove ICG was estimated using a perfusion-limited model of hepatic elimination. Although the influence of the altered flow decreased with increasing ICG dose, the changes in both flow and intrinsic clearance were directly proportional to the increase in liver mass produced by phenobarbital. It may be concluded, therefore, that the influence of phenobarbital on ICG clearance in the rat is due to a larger liver with a proportionate increase in blood flow and not a consequence of the induction of any specific uptake protein.

Effects of alteration of hepatic microsomal enzyme activity on liver blood flow in the rat

The effects of pretreatment with ten daily intraperitoneal injections of phenobarbital (8 mg/100 g/day) 3,4-benzpyrene (1 mg/100 g/day and 3-methyl-cholanthrene (1 mg/100 g/day) and a single injection of SKF-525A (30 mg/kg) on liver blood flow in the rat were studied using radioactive microspheres. Of the hepatic enzyme-inducing agents only phenobarbital caused an increase in total liver blood flow, which averaged 33 per cent, and was associated with a similar increase in liver mass. The polycyclic hydrocarbons caused a small increase in liver mass of 11–15 per cent and no change in liver blood flow. All three agents induced drug-metabolizing enzymes, as judged by zoxazolamine paralysis time. SKF-525A produced no change in liver blood flow or liver mass. Liver blood flow/g of liver was unchanged in all groups. The increase in liver blood flow caused by phenobarbital was due entirely to an increase in flow to the splanchnic organs draining into the portal vein. These results imply that total hepatic blood flow is influenced by the mass of the liver and that the responsible, but as yet unknown, mechanism(s) involve the portal circulation. The different effect of phenobarbital and the polycyclic hydrocarbons on liver blood flow is only one of a number of distinctions between these inducing agents but may account for some of the differences observed in vivo especially with drugs whose clearance is dependent on liver blood flow.

Dimethylbiguanide-evoked increase of anticoagulant elimination not associated with induction of drug metabolizing enzymes

Administration of therapeutic doses of the hypoglycemic drug dimethylbiguanide (metformin) for 10 days to rats failed to lead to increases in aminopyrine N-demethylase, benzo(a)pyrene hydroxylase and epoxide hydrase, activities representative for reactions catalyzed by drug metabolizing microsomal enzyme systems which can be induced by distinctly different groups of drugs. The concentration of cytochrome P-450, the end-oxidase of the microsomal mixed function oxidase(s) was not elevated and its spectral properties were unchanged. Therefore the need for higher doses of the anticoagulant drug phenprocoumon (Marcoumar) and the increase in overall elimination of this drug after treatment of patients with dimethylbiguanide appears not to be due to an induction of drug metabolizing enzymes but rather to the observed increase in liver blood flow.

Increased clearance of antipyrine and d-propranolol after phenobarbital treatment in the monkey. Relative contributions of enzyme induction and increased hepatic blood flow.

The effects of phenobarbital treatment for 12 days on the regional distribution of blood flow and on the disposition of two model drugs, antipyrine and d-propranolol, have been determined in six unanesthetized rhesus monkeys. Phenobarbital significantly increased total hepatic blood flow from 179+/-15 to 239+/-27 ml/min. Liver weight was increased to a similar degree (34%) in phenobarbital-treated animals as compared to control monkeys. The clearance of both antipyrine and d-propranolol was increased and the half-life decreased significantly by phenobarbital. Analysis of the data by a perfusion-limited pharmacokinetic model showed that the changes in antipyrine clearance were due almost entirely to enzyme induction. On the other hand, with d-propranolol, the increase in liver blood flow contributed as much to the enhanced clearance as did the stimulation of drug metabolism. The mechanism by which phenobarbital produces the frequently observed increase in drug clearance, therefore, depends upon the initial clearance value of the drug. For low clearance drugs like antipyrine, clearance changes occur largely as a result of enzyme induction. With higher clearance drugs, the effects of increased hepatic blood flow become progressively more important the greater the initial clearance value.

Changes in liver blood flow during enzyme induction

There is a difference between in vitro and in vivo measurements of the extent of enzyme induction. To explain this disparity we have measured changes in liver blood flow produced by three inducing agents—phenobarbitone (30 mg/kg for 4 days), antipyrine (30 mg/kg for 4 days) and 3,4-benzpyrene (40 mg/kg as a single injection). Flow was measured by a heat exchange method in conscious rats. Liver blood flow increased by 33–175 per cent above control values in rats treated with phenobarbitone and antipyrine but not in those given benzpyrene. The increase in liver blood flow was first seen at 24 hr and remained above control values for 2–8 days after treatment. In similarly operated rats phenobarbitone shortened the sleeping time to 5–10 per cent of control values with a similar time course to the changes in liver blood flow. The maximal velocity of N-demethylation of ethylmorphine increased from 4.9 to 17.2 nm/mg protein/min, the maximal increase occurring 2–3 days after starting phenobarbitone. It is suggested that the increase in liver blood flow may be due to increases in liver weight and enzyme activity.

Splanchnic hemodynamic responses to glucagon.

Glucagon, a substance originally thought exclusively to play a part in carbohydrate metabolism, has during recent years been found to possess several other important properties. Among them are influence on tubular reabsorption of electrolytes, 1 on adrenal medullary secretion, 2 on calcium metabolism, 3 on gastric secretion, 4 and on gastrointestinal motility. 5,6 During the last decade, cardiovascular effects have been added to the increasing list of glucagon characteristics. Shoemaker et al 7 reported an increase in liver blood flow after glucagon administration. They used the sulfobromophthalein (Bromosulphthalein [BSP]) sodium technique to study the hepatic blood flow. The flow increase paralleled the blood glucose rise. Merrill et al 8 demonstrated a vasodilatory effect of glucagon on the splanchnic vascular bed in perfusion experiments. Parmley et al 9 reported an inotropic and chronotropic effect on cardiac activity following glucagon injection in man. In a recent publication, Kock et al, 10 using

Spleen blood flow and splanchnic haemodynamics in blood dyscrasia and other splenomegalies.

1. Splenic blood flow and splanchnic haemodynamics have been studied in twenty patients with splenomegaly due to blood dyscrasia or diseases involving the reticuloendothelial system. Thirteen of these patients had portal hypertension, three had abdominal collaterals on arteriovenography and one oesophageal varices. 2. Total spleen blood flow was increased in all with values up to 1550 ml/min, and associated with this liver blood flows increased up to 2·61 1 min−1 m−2. In four patients the cardiac output was raised. 3. In five patients a raised wedged hepatic vein pressure was found which was solely related to the increase in liver blood flow, but in two others, in whom hepatic histology was abnormal, there was also an increase in postsinusoidal resistance. Nine patients had a raised hepatic pre-sinusoidal resistance. This was related to a greatly increased liver blood flow with portal tract fibrosis and cellular infiltration as possible additional factors. 4. The haemodynamic findings in these patients were similar to those found previously in patients with tropical splenomegaly. In both groups spleen blood flow in ml 100 g−1 min−1 was inversely proportional to spleen size. There were similar increases in total spleen and liver blood flows and in the percentage of patients with an increased pre-sinusoidal resistance. In contrast, in cirrhosis there was no inverse relationship between flow in 1 100 g−1 min−1, and of spleen size, and for the degree of splenomegaly total spleen blood flow was relatively greater.