Plasma levels and negative chronotropic effect of metoprolol following single doses of a conventional and sustained-release formulation

Abstract

Plasma levels and associated reduction in exercise-induced tachycardia have been examined following the administration of single doses of metoprolol in conventional and slow-release tablets at different times to six healthy male subjects. The study was carried out in two parts. Initially, the tablets were given at 9 a.m. and the subjects were studied up to 14 h and then at 24 h. Subsequently, the same doses were given at 9 p.m. and the subjects were studied 12-24 h after drug administration (i.e. 9 a.m.-9 p.m. the next day). After giving the slow-release tablets the peak plasma levels were significantly lower but the drug persisted in the plasma at higher levels than after the conventional tablet. However, the beta-blocking effect was comparable from the two dosages. The results obtained for the period 12-24 h after the evening dose differed from the corresponding values after morning administration in that the plasma levels were higher and the beta-blocking effects more marked. Furthermore, the half-life values calculated from these data were significantly longer.

Lack of evidence for polymorphism in metoprolol metabolism.

“…We have also collected metoprolol AUC data in 113 young, healthy subjects following a single 100 mg oral dose of the film-coated tablet: this data is from our own published work and the published papers and research reports of others (Regdrdh et al, 1975;Kendall et al, 1977;Melander et al, 1977;Quarterman et al, 1979;Kendall et al, 1980;Quarterman et al, 1981;Jack et al, 1982b). Similar data on acebutolol following a single oral dose of 400 mg (Sectral® ) in 34 young, healthy volunteers have also been collected for comparison since this drug is eliminated by a different pathway and no suggestion of polymorphism has ever been made (Gulaid et al, 1981;Jack etal., 1982a,b).…”

Comparison of the pharmacodynamic and pharmacokinetic profiles of single and multiple doses of a commercial slow‐release metoprolol formulation with a new Oros delivery system.

“…The amount of drug reaching the circulation from the two formulations can therefore be considered to be equivalent. a (Leahy et al, 1980) and pindolol (Aellig, 1976) or those administered in special slow release forms for example propranolol, Inderal LA® (Leahy et al, 1980 (Quarterman et al, 1979;Kendall et al, 1980). Although diastolic blood pressure results were not reduced on Day 1, by Day 8 there was an average reduction of8 mmHg over 24 h (range 3 to 13 mmHg).…”

“…Because of its short elimination half-life, slow-release formulations have been developed to allow once-daily dosing while maintaining a clinical effect over a 24 h period. The prolongation of 83-adrenoceptor blockade attainable with the 200 mg slow release formulation (Slow Lopresor ®), has been demonstrated in a number of studies (Quarterman et al, 1979;Kendall et al, 1980). The more conventional matrix type slow-release formulations suffer from the disadvantage that a substantial part of their total content is relatively rapidly released once the core surface is exposed: in the case of Slow metoprolol 50% of the drug is released from the formulation within the first 3 h (Regardh et al, 1975).…”

Comparison of two slow‐release formulations of metoprolol with conventional metoprolol and atenolol in hypertensive patients.

“…Metoprolol is usually prescribed twice daily because its ,-adrenoceptor-blocking effect may not be sustained over 24 h after once daily dosing (Reybrouck et al, 1978;Quarterman et al, 1979). This is in keeping with a short plasma half-life of 3 h (Johnsson et al, 1975).…”