Pharmacokinetics of lidocaine in healthy individuals pretreated with multiple doses of metoprolol.

The effect of pretreatment with multiple doses of 100 mg of metoprolol on the pharmacokinetics of lidocaine has been studied in six young healthy subjects. The lidocaine dose was 100 mg and the infusion time 12 minutes. Metoprolol had no effect on the levels or the time course of lidocaine in the plasma. The disposition characteristics of the antiarrhythmic agent were not significantly altered by metoprolol in these individuals. These results cannot be extrapolated to prolonged infusion of lidocaine in patients with myocardial infarction.

Pharmacokinetics of metoprolol in patients with hepatic cirrhosis.

The selective beta 1-adrenoceptor antagonist metoprolol is eliminated primarily by hepatic metabolism and usually less than 5% of an oral dose is excreted unchanged in the urine. The effects of impaired liver function on the pharmacokinetics of metoprolol were studied in 10 patients with hepatic cirrhosis. All subjects were given single doses of 20mg intravenously and 50mg orally on separate days. The mean fraction of the drug available systematically was 84 +/- 10% in patients and 50 +/- 11% in a control group of 6 healthy subjects (p less than 0.05). The total body clearance of metoprolol in the cirrhotics was 0.61 +/- 0.13L/min and in the controls 0.80 +/- 0.11L/min. These values correspond to elimination half-lives of 7.2 +/- 1.2 and 4.2 +/- 1.1 hours, respectively. The differences were not statistically significant. Impaired liver function had no effect on the volume of distribution of metoprolol. Total clearance was weakly but linearly related to galactose clearance (r2 = 0.52; p less than 0.05), and the half-life was related to serum bilirubin (r2 = 0.74; p less than 0.01).

Plasma concentrations and beta-blocking effects in normal volunteers after intravenous doses of metoprolol and propranolol.

The pharmacokinetics of metoprolol and propranolol in 6 healthy volunteers were compared after an intravenous dose of 10 mg of each drug. The mean t1/2, beta was 3.6 hr for both drugs, but due to a larger volume of distribution, the total body clearance was significantly higher for metoprolol (1.20 liters/min) than for propranolol (0.81 liters/min). The individual pharmacokinetic data were used to calculate the doses required to increase the amount of each drug in the body to 10 and 20 mg at 90 and 180 min respectively after an initial intravenous dose of 5.0 mg. The effect on exercise heart rate was determined 30 min after each dose. After identical doses, the two drugs had similar beta-blocking effects in terms of reducing exercise-induced tachycardia. These effects increased with the dose administered. The plasma levels of propranolol were twice as high as those of metoprolol for identical degrees of beta-blockade. The slope of the regression line for the relationship between the beta-blocking effect and log plasma concentrations was the same for the two drugs.

Plasma levels and pharmacological effects of metoprolol administered as controlled release (Durules) and ordinary tablets in healthy volunteers.

The bioavailability, plasma levels and pharmacological effect of a daily dose of 0.2 g of metoprolol in Durules and in regular 0.1 g tablets have been studied in eight healthy volunteers during steady state conditions. Durules and two 0.1 g metoprolol tablets were given once daily, and one 0.1 g metoprolol tablet was given every 12th hour. The maximum concentration of metoprolol in plasma after Durules was about half of that after two regular tablets. When one metoprolol 0.1 g tablet was administered every 12th hour, an average maximum concentration slightly higher than for the Durules was recorded about one hour after the administration. The minimum concentration of metoprolol during the day was about twice as high after Durules as after the same dose in regular tablets. The dose-corrected area under the plasma concentration vs time curve of Durules was 87 per cent of the b.i.d. regimen of metoprolol in regular tablets and about 75 per cent of two metoprolol 0.1 g tablets once daily. Metoprolol Durules maintained a more even effect on heart rate and systolic blood pressure during exercise during the day than the corresponding daily dose of metoprolol given as two metoprolol 0.1 g tablets once daily or as one metoprolol 0.1 g tablet every 12th hour. After maximum beta-blockade the effect declined by, on average, 0.60 per cent/hour for the Durules and 0.96 per cent for the regular tablet. The exercise heart rate before the morning dose was significantly lower during treatment with Durules and one metoprolol 0.1 g tablet b.i.d. than during the placebo period. The interaction of metoprolol with the effect of adrenaline (0.09 microgram x kg-1 x min-1, infused at 2, 3.5 and 5 hrs after metoprolol administration) on the diastolic blood pressure was more pronounced when two ordinary 0.1 g metoprolol tablets were administered once daily than for the corresponding dose in Durules, this probably reflecting a difference in degree of action of metoprolol on the vascular bed for Durules and regular metoprolol tablets in identical doses.

The effect of impaired renal function on the plasma concentration and urinary excretion of metoprolol metabolites.

Plasma concentration and urinary excretion of total and 2 active metabolites of metoprolol have been studied in patients with varying degrees of renal impairment and in healthy subjects after intravenous and oral administration of 20 and 50 mg of 3H-metoprolol tartrate respectively. Renal clearance of total metabolites correlated directly with 51Cr-EDTA clearance (r = 0.95, p less than 0.001). A reduction of glomerular filtration rate (GFR) by 70 to 80% increased the elimination half-life of total metabolites and of the active metabolite alpha-hydroxymetoprolol about 3-fold. Significant accumulation was, however, only observed in the patients with a GFR of about 5 ml/min. Even in these patients, the contribution of alpha-hydroxymetoprolol to the beta-adrenoceptor blocking effect of metoprolol will be negligible. The second active metabolite studied is eliminated via biotransformation, and the urinary excretion as well as the plasma concentration of this metabolite were extremely low in comparison with those of the parent drug.

Pharmacokinetic and pharmacodynamic properties of metoprolol in patients with impaired renal function.

The pharmacokinetics of metoprolol have been studied in a group of patients with varying degrees of renal impairment and in healthy subjects after administration of 20 mg of metoprolol tartrate intravenously and 50 mg orally in a single dose and during steady-state conditions. There were no significant differences in the extent of bioavailability or rate of elimination of the drug between the 2 groups. The fraction of the oral dose systemically available during steady-state was 59 +/- 9% in the renal patients and 55 +/- 7% in the control group. Total body clearance in the patients with renal failure was 1.0 +/- 0.1 L/min and in the healthy subjects it was 0.8 +/- 0.1 L/min. The corresponding values for the elimination half-life were 4.6 +/- 1.2h and 4.1 +/- 1.0h, respectively. The beta-adrenoceptor blocking effect of metoprolol (determined as percent reduction of exercise heart rate) did not differ significantly between the 2 groups during steady-state conditions. The effect on exercise heart rate was linearly related to the log of the plasma concentration of metoprolol. The relationship was identical for the single dose and during steady-state conditions, indicating that accumulation of metabolites in patients with renal failure does not influence the beta-blocking properties of metoprolol.

Bioavailability and disposition of metoprolol and hydrochlorothiazide combined in one tablet and of separate doses of hydrochlorothiazide.

1. The plasma levels and the urinary excretion of hydrochlorothiazide (HCT) have been studied after administration of single doses of 12.5 and 25 mg of the drug in solution and in combination with 100 mg of the selective beta 1-adrenoreceptor antagonist metoprolol in a rapidly dissolving tablet. 2. Metoprolol did not significantly influence the bioavailability or the time-course of HCT. 3. HCT had no significant effect on the time-course or the plasma levels of metoprolol. The average half-life, 4.4 +/- 0.9 h, is about the same as previously observed for separate doses of this drug. 4. It seems unlikely that repeated doses of the combination product studied will lead to biopharmaceutic or pharmacokinetic interactions of clinical importance.

Haemodynamic effects and pharmacokinetics of a new selective beta1-adrenoceptor agonist, prenalterol, and its interaction with metoprolol in man.

The haemodynamic effects of the selective beta1-adrenoceptor agonist prenalterol were studied in healthy subjects before and after therapeutic doses of the selective beta1-adrenoceptor blocker metoprolol. Plasma levels of the drugs were also determined in order to calculate certain pharmacokinetic variables. Intravenous infusion of prenalterol 0.13, 0.25 and 0.50 mg induced a dose-dependent decrease in total electromechanical systole (QA2) and pre-ejection period (PEP). The effect on left ventricular ejection time (LVET) was not significant. Increases in systolic blood pressure and heart rate were dose-dependent. Diastolic blood pressure did not change significantly. When metoprolol had been administered in a cumulative dose of 150 mg (mean maximal plasma level, 284 nmol/l) prenalterol had to be administered in doses that were twelve times higher than before the beta-blocker in order to induce the same haemodynamic effects. Prenalterol was rapidly distributed with an average half life of 8 min. This indicates that distribution equilibrium will be achieved within 30 min after intravenous administration. The overall elimination rate in the post-distributive phase corresponded to an average half life of 2.0 h.

Effect of long-term administration of various alcoholic beverages on the in vitro incorporation of 3H-leucine into proteins in rat cerebral cortex, cerebellum and liver.

The incorporation of 3H-leucine into protein from anterior and posterior cerebellum, cerebral cortex and liver was studied in rats given 50% of calories as ethanol, brandy, whisky, gin, red wine or isocaloric amounts of glucose together with diets with moderate or low protein-vitamin content for 8--9 months. Higher incorporation rates were usually observed with higher protein-vitamin administration. Red wine and brandy rats usually had the highest, ethanol and gin rats usually the lowest incorporation rates. The incorporation rate thus increased with amount of congeners present.

The effect on the rat liver of long-term administration of different alcoholic beverages together with inadequate diets.

Rats were given 36 per cent of calories as ethanol, gin, brandy, whisky or red wine together with hypocaloric (25 per cent of normal), hypocaloric--low-protein--highfat, or hypocaloric--low vitamin diets for several months and compared with rats given isocaloric amounts of glucose instead of alcohol. In spite of high mortality rate no severe liver lesions occurred, especially no cirrhosis. Congeners present in different alcoholic beverages therefore seem to lack important hepatotoxic effects at least in the rat.

Effects of long-term administration of alcoholic beverages on the kidney, heart, skeletal muscle and pancreas of rats. A histological study.

No pathological changes in the pancreas, kidneys or skeletal muscle were found in rats maintained for 8 to 9 months with a diet in which alcohol made up 50% of the total calories. An increase of the dietary fat content to 38% did not cause any fatty infiltration of the myocardium.

Effect of long-term administration of different hard liquors and red wine on the rat liver. A histological and biochemical study.

Male rats were given 50 per cent of calories as ethanol, whisky, brandy, gin and red wine for 8-9 months together with moderate or low protein and vitamin supply. Histological studies at sacrifice failed to detect signs of hepatotoxicity, but biochemical studies indicated that at least red wine and whisky produced more undesirable effects on the liver than ethanol.