Summary
Although β-Blockers are structurally closely related, there are marked differences in the extent of metabolism, related mainly to relative lipophilicity. Lipophilic β-Blockers are metabolized by C-oxidative pathways and glucuronidation. Metabolism of lipophilic β-Blockers is important in determining pharmacokinetics, formation of active metabolites, stereoselectivity and isomer preference, and interphenotypic variation. The oxidative clearance of metoprolol, timolol and bufuralol is regulated/influenced by the debrisoquine hydroxylation gene locus. The metabolism of these lipophilic β-Blockers thus exhibits polymorphic characteristics, there being significant interphenotype differences in pharmacokinetics (bioavailability, peak plasma level, plasma terminal t1/2) between the poor and extensive metabolizers of debrisoquine. There are similar interphenotype differences in β-blocker pharmacodynamics in terms of β-blockade. A number of adverse effects of lipophilic β-Blockers have been hypothesized to predominate in the poor metabolizer phenotype including unacceptable bradycardia, loss of cardioselectivity, greater CNS side-effects, and interactions with drugs metabolized by the same polymorphic systems. However, objective evidence for this is lacking.
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Smith, R.L. Polymorphic metabolism of the β-adrenoreceptor blocking drugs and its clinical relevance. Eur J Clin Pharmacol 28 (Suppl 1), 77–84 (1985). https://doi.org/10.1007/BF00543715
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DOI: https://doi.org/10.1007/BF00543715