Gillis Johnsson

Pharmacokinetic studies on the selectiveβ1-receptor antagonist metoprolol in man

The pharmacokinetics of3H-metoprolol, a new selective β1-receptor antagonist, have been studied in healthy volunteers by following the plasma concentrations and the urinary excretion of the unchanged compound and its total radioactive metabolites after oral and intravenous administration. The compound was rapidly and completely absorbed after oral administration, and about 40% of the dose reached the systemic circulation. The estimated half-life of the absorption process was 10 min. Metoprolol was extensively distributed to extravascular tissues, with the half-life of the distribution phase close to 12 min. About 95% of the dose was excreted in the urine within 72 hr, mainly in metabolized form. The elimination halflife of the compound was close to 3 hr as was also the half-life of the total metabolites after oral administration. After intravenous administration, the elimination half-life of the metabolites was raised to 5 hr, indicating that the route of administra tion might influence the metabolic pathways of the parent compound.

Pharmacokinetic and Pharmacodynamic Properties of Metoprolol in Patients with Impaired Renal Function

SummaryThe pharmacokinetics of metoprolol have been studied in a group of patients with varying degrees of renal impairment and in healthy subjects after administration of 20mg of metoprolol tartrate intravenously and 50mg 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 ± 0.1L/min and in the healthy subjects it was 0.8 ± 0.1L/min. The corresponding values for the elimination half-life were 4.6 ± 1.2h and 4.1 ± 1.0h, respectively.The β-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 β-blocking properties of metoprolol.

Combined pharmacokinetic and pharmacodynamic studies on alprenolol and 4-hydroxy-alprenolol in man

Abstract The effects of orally (100 mg) and intravenously (10 mg) administered alprenolol on the heart rate of 4 exercising healthy volunteers were correlated with the plasma concentrations of alprenolol and its metabolite 4-OH-alprenolol. The metabolite was recovered in plasma after both routes of alprenolol administration and was eliminated from the body at the same rate as alprenolol ( t 1 2 ≅ 3 h ). Infusion of 4-OH-alprenolol (10 mg) significantly reduced the heart rate during exercise. The results indicate that orally administered alprenolol forms the active metabolite 4-OH-alprenolol in sufficiently large amounts to significantly influence the effect of the parent drug. The “first pass” elimination of the oral alprenolol dose was about 90 per cent.

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

Summary 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,β 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.

Studies on the mechanism of the vasoconstrictor effect of angiotensin II in man

Abstract Intravenously infused angiotensin II elicited a vasoconstriction in the hand. This effect was 1) inhibited by low doses of phenoxybenzamine and guanethidine infused into the brachial artery, 2) accompanied by signs of increased activity in the vasoconstrictor nerves to the hand. The findings indicate that in man, as has recently been demonstrated in animals, angiotensin II induces an increased sympathetic activity which seems to be responsible for part of its vasoconstrictor effect in the hand.