Pharmacokinetic and pharmacodynamic studies of single oral doses of metoprolol in normal volunteers

Abstract

The effects of three orally administered doses of metoprolol, a beta 1 adrenoceptor antagonist, on resting blood pressures, resting pulse rates and heart rates during maximum exercise have been compared with those of placebo in six healthy male volunteers.The differences in blood pressures and pulse rates at rest were small and only statistically significant at isolated time points during the 24 hours study period. The reduction in exercise heart rates reached maximum values at 1.5 to 2 hours after drug administration and thereafter increased linearly with time. The zero-order rate constants for this process were similar for each of the three doses investigated.The mean durations of beta blockade after oral administration of 50,100 and 200 mg. were 13.2,16.9 and 19.2 hours, respectively. An apparent linear relationship between exercise heart rate and logarithm of the drug concentration in plasma was observed for each dose studied.The relationship between area under the plasma concentration curve and dose is statistically compatible with a linear function in the range 50 to 200 mg. The actual areas, however, suggest the possibility of an increased bioavailability for the higher dose.The significance of these results is discussed in relation to the possible use of a single daily dosage regimen in the treatment of angina pectoris and hypertension. IntraductionMetoprolol (Lopresor®, Ciba-Geigy) is a selective beta-adrenergic receptor blocking drug which has been shown to be effectivein the treatment of angina pectoris (1) and hypertension (2). One of the main problems in the management of these conditions is lack of compliance by patients with long-term oral therapy. Compliance is influenced by a number of factors, including the nature and duration of the illness, the treatment administered, the incidence and severity of drug related side-effects,and the frequency of daily dosage.The incidence of side-effectswith beta-receptor blocking drugs is low and unlikely to reduce compliance. Frequency of dosing, however, appears to be an important determinant (3) and simplification of the dosage Send reprint requests to: regimen could lead to a significantimprovement in overall compliance. Most beta-blocking drugs are recommended to be taken two, three or four times a day depending on the elimination half-life of the drug in plasma. Recent studies (4) (5) with other beta-blocking drugs have shown that effective control of blood pressure can be achieved with once daily dosage regimens. Before recommending a similar regimen for metoprolol it would be desirable to have data comparing the efficacy of different dosage regimens in the treatment of angina and hypertension.In the present study the effects of single oral doses of 50, 100 and 200 mg. metoprolol on resting blood pressures, pulse rate and heart rate during maximum dynamic exercise, were compared with those of placebo in healthy volunteers. The plasma concentration and urinary excretion profiles for the three oral doses of metoprolol were also compared to determine whethe...

Influence of nitrendipine and verapamil on plasma levels, urinary excretion, and beta-blocking effect of metoprolol

“…The inhibition of exercise-induced tachycardia observed in the present study following administration of metroprolol alone is comparable to values described in the literature [15]. As 12 hours after dosing of the betablocker, a distinct inhibition of exercise tachycardia by about 10% was still observed, it appeared to be reasonable to also determine this hemodynamic parameter on combination therapy with the calcium antagonists.…”

Osmotically controlled‐delivery of metoprolol in man: in vivo performance of Oros systems with different durations of drug release.

“…Metoprolol is subject to a significant first-pass effect (Reg'ardh & Johnsson, 1980) which decreases with increasing doses of conventional tablets (Kendall et al, 1977). This effect has been attributed to saturation of first-pass metabolism by transiently high drug concentrations in the hepatic circulation during the absorption process.…”

Proceedings of the British Pharmacological Society

“…Interestingly the plasma half lives for the closely related compound metoprolol are in the same ranking order, but are much shorter (rat 0.62 + 0.07 h, dog 1.61 h, Borg, Fellenius, Johansson & Wallborg, 1975, and man 3.3 + 0.1 h, Kendall, Brown, Grieve & John, 1977) and this is in all probability due to the absence of the cyclopropyl group which is present in SL 75 212. A previous study has shown that elderly human subjects and rats show an increased sensitivity to warfarin (Shepherd, Hewick, Moreland & Stevenson, 1977) spectively (Shearer, Barkhan & Webster, 1970).…”