Comparison of two long‐acting preparations of metoprolol with conventional metoprolol and atenolol in healthy men during chronic dosing.

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150

112

1 The metabolism of metoprolol was studied in 143 unselected hypertensive patients and in 10 families. 2 The loglo metoprolol to a-hydroxymetoprolol urinary ratio was bimodally distributed and was correlated with the debrisoquine oxidation phenotype (rs = 0.81, P < 0.001).3 The results of the pedigree study were compatible with poor hydroxylation of metoprolol being inherited as an autosomal recessive trait. 4 The major urinary metabolite of metoprolol metabolism was H117-04, the endproduct of O-dealkylation. The distribution of the log1o metoprolol to H117-04 (M/H117-04) urinary ratio was unimodal. However, there was a significant correlation between this ratio and the debrisoquine oxidation phenotype (rs = 0.68, P < 0.001) and poor metabolisers of debrisoquine (PMs) were concentrated at the upper end of the range of M/H117-04 values. 5 These results indicate that both the a-hydroxylation and O-dealkylation of metoprolol are under polymorphic control of the debrisoquine type. 6 Plasma concentrations of metoprolol were about three times higher in PMs than in extensive metabolisers of debrisoquine (EMs) at 3 h after dosing. 7 In a sub-group of 24 subjects, all seven PMs but only two EMs showed more than a 10% reduction in post-exercise heart rate at 24 h after dosing.

Section: Exercise Testsmentioning

confidence: 99%

Metoprolol metabolism and debrisoquine oxidation polymorphism‐ population and family studies.

McGourty¹,

Silas²,

Lennard³

et al. 1985

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150

112

“…In EM the mean elimination halflife was similar to that reported by others (2.8 h) but it was much longer in PM (7.6 h). (Freestone et al, 1982).…”

Section: Metoprololmentioning

confidence: 99%

“…'long-acting' formulations of metoprolol was associated with marked variability in 8-adrenoceptor blockade 24 h after a 200 mg dose, and with insignificant f3-adrenoceptor blockade in the most extensive metabolisers (metabolic ratio < 1) (Freestone et al, 1982). Therefore, these formulations may offer no advantage over the conventional tablets since they too must be prescribed twice daily in angina unless the oxidation phenotype is known.…”

Section: Propranololmentioning

confidence: 99%

Polymorphic metabolism of beta‐adrenoceptor antagonists.

Silas¹,

Lennard²,

Tucker³

et al. 1984

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Most beta‐adrenoceptor blockers undergo extensive oxidative metabolism. The evidence for polymorphism of the debrisoquine type is reviewed. The AUC and half‐life of metoprolol were considerably greater in poor metabolisers (PM) of debrisoquine than in extensive metabolisers (EM). Metoprolol alpha‐hydroxylation is impaired and O‐dealkylation must also be affected. Polymorphism in the former route has been demonstrated in a population of 143 patients to be directly related to debrisoquine phenotype. Bufuralol AUC and half‐life are much higher in PM than EM subjects. Hydroxylation at the 1 and 4 positions are affected. Genetic polymorphism for 1‐hydroxylation has been shown in family and population studies. Propranolol 4‐hydroxylation is defective in PM subjects of debrisoquine but propranolol AUC is not related to phenotype, presumably because other major pathways are unaffected. Oxidation phenotype correlates well with intensity and duration of beta‐ adrenoceptor blockade after metoprolol, PM subjects requiring only once‐ daily dosing. However, in EM subjects twice‐daily dosing is required even if slow release preparations are used, since plasma metoprolol concentrations may remain negligible 24 h after dosing. The beta‐ adrenoceptor blocking effects of propranolol and bufuralol are unlikely to be influenced by oxidation status. Anecdotal reports of toxicity arising in PM subjects taking metoprolol or propranolol need to be substantiated. However, vomiting after the administration of bufuralol often occurs in poor metabolisers. Metabolic interactions with drugs sharing the same enzyme system are discussed. Debrisoquine and bufuralol competitively inhibit each other's metabolism in vitro. (ABSTRACT TRUNCATED AT 250 WORDS)

“…Its short elimination half-life has led to the development of a slow-release formulation of the polymer-matrix type (Lopresor SR®). Clinical studies have shown that this formulation is effective and well tolerated when administered once daily (Nievel & Harvard, 1981) but its ability to sustain statistically significant 3-adrenoceptor blockade throughout 24 h has recently been questioned (Freestone et al, 1982).…”

Section: Introductionmentioning

confidence: 99%

A multiple dose pharmacokinetic and pharmacodynamic evaluation of conventional and 19/285 Oros formulations of metoprolol in healthy volunteers.

Grainger¹,

John²,

Shotton³

et al. 1985

1 Plasma metoprolol concentrations and haemodynamic effects have been measured in six healthy male volunteers during once daily dosing with a 19/285 Oros system and twice daily dosing with 100 mg conventional tablets, on two separate occasions. 2 Plasma drug concentrations throughout the day varied less with the Oros than with the conventional tablet regimen. Predosing concentrations were also higher with Oros but areas under the curve, after correcting for the differences in dose, were similar for the two preparations. 3 Inhibition of exercise tachycardia was drug concentration dependent and was smoothly controlled through the day only with the Oros preparation. Predosing effects at steadystate were also greater for the Oros regimen. The decline in mean blood pressure, however, showed the same daily pattern for both regimens, and no significant differences were detected between Oros and conventional tablet treatments. 4 The smoothness of the plasma profiles after Oros confirmed the controlled-release performance of the system in vivo and indicates its potential in the treatment of angina, cardiac arrhythmias and wherever it is important not to jeopardize steady selectiveadrenoceptor blockade.