Oxidation phenotype and the metabolism and action of beta-blockers

Abstract

Variability in response to some drugs such as debrisoquine can be attributed to genetic polymorphism of their oxidative metabolism. Most beta-adrenoceptor antagonists (beta-blockers) are extensively metabolised via oxidative routes. Anecdotal reports of high plasma concentrations of certain beta-blockers in poor metabolisers of debrisoquine (PM) have claimed that their oxidation is under polymorphic control. Controlled studies have shown that debrisoquine oxidation phenotype is a major determinant of the metabolism, pharmacokinetics and some of the pharmacological actions of metoprolol, bufuralol and timolol. The PM phenotype is associated with an increased drug bioavailability, a prolongation of elimination half-life and more intense and sustained beta-blockade. Phenotypic differences were also noted in the pharmacokinetics of the enantiomers of metoprolol. In vivo and in vitro work has identified some of the metabolic pathways which are subject to the defect, namely, the alpha-hydroxylation and the O-dealkylation of metoprolol and the 1'-hydroxylation of bufuralol. In contrast, the pharmacokinetics and pharmacodynamics of propranolol which is also extensively oxidised, are not related to debrisoquine polymorphism, although 4'-hydroxypropranolol formation is lowered in PM subjects. The clinical significance of impaired elimination of beta-blockers is unclear. If standard doses of beta-blockers are used in PM subjects, they may be susceptible to concentration-related adverse reactions and they may also require lower and less frequent dosing for control of angina pectoris.

Polymorphic metabolism of beta‐adrenoceptor antagonists.

“…This was confirmed subsequently in a larger study ( Figure 2) (Lennard et al, 1983). Not only was there complete concordance with respect to debrisoquine phenotype, but the metabolic ratios for debrisoquine and metoprolol were highly correlated in the group as a whole (rs = 0.81, P < 0.0001) (unpublished data).…”

Quinidine: potent inhibition of sparteine and debrisoquine oxidation in vivo.

“…Poor metabolizers of sparteine and debrisoquine having an autosomal recessive trait show a decreased metabolizing capacity of certain drugs leading to elevated plasma concentrations (Lennard, 1985). Susceptible drugs include ,Badrenoceptor antagonists and tncyclic antidepressants.…”

“…Genetic deficiencies in the oxidative metabolism of sparteine and debrisoquine in man are well documented (Eichelbaum, 1984;Kalow, 1984). Poor metabolizers of sparteine and debrisoquine having an autosomal recessive trait show a decreased metabolizing capacity of certain drugs leading to elevated plasma concentrations (Lennard, 1985). Susceptible drugs include ,Badrenoceptor antagonists and tncyclic antidepressants.…”

The Polymorphic Oxidation of ??-Adrenoceptor Antagonists

“…The contribution of debrisoquine polymorphism to the variability in the plasma concentrations of certain ,a-blockers has been estimated by linear regression (Lennard 1985b). It was found that for metoprolol, timolol, propranolol and atenolol, 94, 61,8 and 0%, respectively, of the variance in AUC was related to the debrisoquine to 4-hydroxydebrisoquine ratio.…”