Apparent Liver Blood Flow Research Articles

The interactions between nisoldipine and two beta‐adrenoceptor antagonists‐atenolol and propranolol.

1. The interactions between the dihydropyridine calcium antagonist nisoldipine and two beta-adrenoceptor blocker drugs (atenolol and propranolol) were investigated in two groups of healthy normotensive subjects. 2. The steady state plasma concentrations of both beta-adrenoceptor blockers were significantly altered by the addition of nisoldipine: for propranolol there were significant increases in Cmax, by about 50%, and in AUC by about 30% and for atenolol there was a significant increase in Cmax, by about 20%. 3. The addition of nisoldipine was also associated with significant changes in apparent liver blood flow (measured by indocyanine green clearance) from 1.4 to 2.4 l min-1 in the atenolol group and from 1.3 to 2.3 l min-1 in the propranolol group. 4. Both nisoldipine-beta-adrenoceptor blocker combinations were associated with small enhanced blood pressure reductions e.g. from 104/60 with atenolol alone to 98/50 mm Hg with the combination but there was no alteration to the extent of beta-adrenoceptor blockade (as assessed by bicycle ergometry). 5. This pharmacodynamic profile in healthy normotensives is consistent with the known therapeutic efficacy of such combination treatments in patients with hypertension and angina. 6. It is suggested that there is a pharmacokinetic component to the efficacy of this type of combination, perhaps reflecting vasodilator-induced changes in drug absorption and/or hepatic extraction.

Clinical Studies with the Potassium Channel Activator Cromakalim in Normotensive and Hypertensive Subjects

Eight normotensive subjects received single and multiple doses of cromakalim (1 mg) and placebo in a randomised double-blind cross-over study to examine general tolerance to cromakalim and its effects on blood pressure (BP), heart rate (HR), and pressor responses to norepinephrine (NE) and angiotensin II (AII). In a second study, 10 hypertensive patients whose BP control was unsatisfactory with atenolol 50-100 mg received additional treatment with placebo followed by cromakalim 1 mg daily for 4 weeks. Assessments were made of BP, HR, apparent hepatic blood flow and renal blood flow (RBF), pulmonary function, and the pharmacokinetics of atenolol. Cromakalim was generally well tolerated in both normotensive and hypertensive subjects. In the normotensive group, cromakalim produced a reflex increase in HR without any detectable decrease in BP: average (placebo-subtracted) increases in HR at 4 h were 16 beats/min with subjects in an erect position after the single dose and 14 beats/min after 7 days. Cromakalim had no effect on pressor responses to NE and AII. Addition of cromakalim to atenolol was associated with modest further reductions in BP between 0.5 and 3 h after drug administration, with maximal reductions of 21/14 mm Hg (subjects in supine position) 2 h after the first dose. Cromakalim had no effect on apparent liver blood flow and RBF, pulmonary function, and the steady-state pharmacokinetics of atenolol. Single and multiple 1-mg doses of cromakalim are well tolerated but are associated with only modest vasodilator activity.

Hepatic drug clearance: the effect of age using indocyanine green as a model compound.

The hepatic extraction ratio and clearance of indocyanine green (ICG) were determined and used to derive apparent liver blood flow in nine subjects between the ages of 22 and 83 years. There was no correlation between the hepatic extraction ratio of ICG and age (rs = -0.435, NS). There was a significant negative correlation between both ICG clearance and age (rs = -0.710, P less than 0.05) and apparent liver blood flow and age (rs = -0.750, P less than 0.05). These results validate the comparison of liver blood flow values derived from ICG clearance in humans over a wide age range and confirm that liver blood flow does fall with age.

Apparent liver blood flow during pregnancy: a serial study using indocyanine green clearance

Serial measurements of apparent liver blood flow and cardiac output were performed in 12 women at 12-14, 24-26 and 36-38 weeks of pregnancy and then at 10-12 weeks after delivery. Apparent liver blood flow was calculated from indocyanine green clearance. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic valve. Postnatal apparent liver blood flow was 1.81 l/min and no significant change was demonstrated during pregnancy. In contrast cardiac output decreased from 7.46 l/min at 36-38 weeks gestation to 4.90 l/min after delivery. Apparent liver blood flow accounted for 24% of cardiac output during pregnancy. This increased to 37% after delivery.

The contribution of nisoldipine-induced changes in liver blood flow to its pharmacokinetics after oral administration.

1. The pharmacokinetics of nisoldipine (10 mg) was assessed in 10 healthy subjects after single dose and multiple dose oral administration. Apparent liver blood flow was measured, using ICG before and during the absorption phase of nisoldipine. 2. Apparent liver blood flow was increased both on acute and short-term administration of nisoldipine, basal flow being lower on multiple dosing than on acute administration (P less than 0.02). 3. A positive relationship was found between the increase in apparent liver blood flow during absorption of nisoldipine and the flow-dependent part of the total AUC of nisoldipine. 4. The findings of this study indicate that a variable liver blood flow response during the absorption phase of nisoldipine contributes to the pharmacokinetic variability of the drug, both on acute and multiple dose administration.

The influence of infusion rate on the pharmacokinetics and haemodynamic effects of nisoldipine in man.

1. The pharmacokinetics and haemodynamic effects of nisoldipine on long term i.v. infusion of 2.40 mg and 9.59 mg in 25 h were studied in six healthy subjects. Liver blood flow at 0.8 and 24 h was assessed by measuring indocyanine green (ICG) clearance. 2. After high-dose nisoldipine, systemic clearance was 0.99 +/- 0.16 1 min-1, volume of distribution was 5.8 +/- 1.5 1 kg-1 and elimination half-life was 10.7 +/- 2.4 h. The pharmacokinetic parameters were similar after low-dose nisoldipine. 3. No significant changes in apparent liver blood flow were observed after either high-dose or low-dose nisoldipine. 4. Systolic blood pressure did not change, whereas diastolic blood pressure decreased by approximately 10% during both treatments. Maximal increase in heart rate was approximately 37% at high-dose infusion, whereas this was one half lower during the low-dose regimen. 5. Increased infusion rate results in an unfavourable shift in the haemodynamic effect profile of nisoldipine.

Immediate Effect of Omeprazole and Cimetidine on Apparent Liver Blood Flow in Man

In healthy human subjects, cimetidine reduces plasma clearance of indocyanine green (ICG) by approximately 25% (1). This reduction should reflect a similar decrease in liver blood flow (2) and it is suggested that this effect is mediated by the vascular H2-receptors. This finding has clinical implications in the management of patients with severe liver disorders. Omeprazole, a new suppressor of gastric acid secretion, is an inhibitor of the proton pump in the parietal cell. Omeprazole has no influence on the H2-receptors. As its effect on liver blood flow is unknown, it was decided to study the effect of omeprazole and cimetidine on apparent liver blood flow in healthy human subjects.

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.

The influence of captopril, the nitrates and propranolol on apparent liver blood flow.

Indocyanine green estimated apparent liver blood flow was measured in normal volunteers following glyceryl trinitrate, propranolol, isosorbide mononitrate and captopril. Glyceryl trinitrate and propranolol significantly reduced apparent liver blood flow. Isosorbide mononitrate did not alter apparent liver blood flow or produce an additional reduction in apparent liver blood flow when combined with propranolol. Captopril did not alter apparent liver blood flow despite a significant fall in mean arterial pressure and rise in plasma renin activity. Captopril and isosorbide mononitrate if shown to reduce portal pressure, do so without a fall in apparent liver blood flow.

Cimetidine on apparent liver blood flow

Cimetidine on apparent liver blood flow

Effects of chronic oral cimetidine on apparent liver blood flow and hepatic microsomal enzyme activity in man.

Cimetidine 200 mg three times daily and 400 mg at night was given to 10 subjects for four weeks. Apparent liver blood flow was measured by indocyanine green clearance and microsomal enzyme activity by antipyrine clearance, before and after cimetidine. There was no reduction in indocyanine green clearance but antipyrine clearance, as expected, was significantly reduced by 15% at four weeks. Chronic cimetidine treatment does not reduce apparent liver blood flow and is therefore unlikely to be of use in the treatment of portal hypertension. The cimetidine associated hepatic enzyme inhibition appears to persist with prolonged treatment. Therefore patients on chronic cimetidine remain vulnerable to certain drug interactions.

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.

The effect of indoramin infusion on apparent liver blood flow in man.

The effect of indoramin infusion on apparent liver blood flow in man.

Epoprostenol (prostacyclin,PGI 2) increases apparent liver blood flow in man

When epoprostenol (prostacyclin, PGI 2) is given by infusion to man, cardiac output is increased, and it appears that the gastrointestinal tract may receive a disproportionate share of this. We have used the clearance of indocyanine green dye to estimate liver blood flow in 8 healthy subjects. During an infusion of PGI 2 at a dose of 5 ng/kg/min, apparent liver blood flow increased from 925 ± 220 ml/min (Mean ± s.d) to 1320 ± 453 ml/min, an average increase of 41.1%. Significant changes in heart rate, headache, facial flushing, systolic blood pressure, and pulse pressure were noticed. We suggest that endogenous epoprostenol (PGI 2) May be of importance in the physiological regulation of liver blood flow in man. As this dose of epoprostenol could be tolerated readily, epoprostenol therapy could prove a therapeutic advance in some liver disorders, particularly liver transplantation, and possibly in the therapy of certain drug overdoses.

Effect on apparent liver blood flow of histamine-receptor blockers and inhibition of prostaglandin synthesis.

We have recently shown that histamine H2-receptor blockade with cimetidine reduces apparent liver blood flow. To determine the effects of inhibition of prostaglandin synthesis and of H1-receptor blockade and of their additive effects when combined with cimetidine (600 mg), we estimated liver blood flow from the clearance of a single dose (0.5 mg/kg) of indocyanine green (ICG) in six healthy subjects after indomethacin (50 mg. three times during 24 hr) and chlorpheniramine (8 mg. three times during 24 hr). Indomethacin and chlorpheniramine reduced ICG estimated liver blood flow by 18 +/- 3% and 13 +/- 4% (mean +/- SEM). When cimetidine was added to indomethacin or chlorpheniramine, the reductions in flow of 22 +/- 6% and 19 +/- 5% were not significantly greater than that after indomethacin, chlorpheniramine, or cimetidine alone (16 +/- 6%). These data suggest that both histamine acting through H1- and H2-receptors and prostaglandins may influence liver blood flow in man and are consistent with evidence from animal experiments that suggest a role for prostaglandins in H2-mediated vascular responses.

Propranolol disposition in renal failure.

1 Previous studies of propranolol disposition in renal failure have been conflicting. 2 Using simultaneous administration of [3H]-propranolol intravenously and unlabelled propranolol orally the principal determinants of drug distribution were calculated in normals, patients with severe renal impairment (creatinine clearance 14.5 +/- 2.8 ml/min) but not on haemodialysis and patients on haemodialysis (creatinine clearance less than 5 ml/min). 3 The effect of haemodialysis on propranolol binding and free fraction was also examined. The percentage of propranolol unbound rose from 7.1% to 9.9%. (P less than 0.001) 20 min following heparinization and beginning haemodialysis. This was accompanied by a large rise in free fatty acids from 0.567 +/- 0.059 to 3.326 +/- 0.691 mumol/ml (P less than 0.005). 4 The blood to plasma concentration ratios of propranolol were significantly higher in patients with renal failure (P less than 0.02) and on haemodialysis (P less than 0.001) and were significantly negatively correlated (P less than 0.001) with the haematocrit. 5 Although the half-life propranolol was significantly shortened in the patients with renal failure (P less than 0.02), there was no change in the apparent liver blood flow, extraction ratio or the principal determinants of steady-state drug concentrations in blood namely oral and intravenous clearance from blood. 6 There is, therefore, no pharmacokinetic basis to adjust the dosage of propranolol in patients with renal failure.

Influence of age and smoking on drug kinetics in man: studies using model compounds.

The effect of advanced age on drug disposition and response is the subject of an increasing number of research studies. Cigarette smoking and other environmental factors have been shown to influence the metabolism of some drugs. Studies of the effect of age on the pharmacokinetics of antipyrine, indocyanine green and propranolol indicate that the association of increased drug metabolism and smoking occurs predominantly in the young and that apparent liver blood flow declines with age regardless of smoking habits. This age related effect of smoking on drug metabolism may reflect a reduced capacity for hepatic enzyme induction in the elderly. The relative importance of age related alterations in the intrinsic drug metabolising ability of the liver and in liver blood flow depend on the pharmacokinetic characteristics of the drug being investigated.

Effects of age and cigarette smoking on propranolol disposition

The effects of age and cigarette smoking on the disposition of propranolol have been investigated in 27 normal men, aged 21 to 73 yr. The drug was administered orally (80 mg) every 8 hr and 40 µCi intravenous 3H‐propranolol were administered simultaneously with the seventh dose. Labeled and unlabeled propranolol concentrations were determined in serial blood samples obtained over the next 8 hr. Subgrouping the oral blood concentration/time data according to age (younger or older than 35 yr) showed that the mean levels in the older group were as much as twofold those in the younger group, and that the terminal half‐life (t½β) was prolonged with age (4.19 ± 1.38 vs. 5.05 ± l.36 hr, mean ± SD; p = 0.03). Substratification of cigarette smokers (>10 cigarettes daily) from nonsmokers indicated that the mean levels in the nonsmokers were 200% higher but there was no t½β difference. Despite the considerable interindividual variability, there was a trend for the weight‐normalized, average steady‐state levels to be lower in smokers than in nonsmokers, with the difference becoming smaller with increasing age. Analysis of the data indicated that the intrinsic total clearance of propranolol decreased with age only in the smokers, and toward the constant value of the nonsmokers, while apparent liver blood flow declined equally with age in both groups. Consequently, systemic‐clearance correlated negatively with age in the smokers and in the group as a whole. No age relationships were found in the volume of distribution and, thus, correlations of age and t½β were of the same order as those of systemic clearance. No changes were observed in systemic availability or plasma binding with aging in either group. It, therefore, appears that cigarette smoking habits are important in the altered steady‐state kinetics of propranolol that develops with aging. The results are consistent with a decreased induction of drug‐metabolizing enzyme with aging.