Polymorphic metabolism of the beta-adrenoreceptor blocking drugs and its clinical relevance.

Although beta-blockers are structurally closely related, there are marked differences in the extent of metabolism, related mainly to relative lipophilicity. Lipophilic beta-blockers are metabolized by C-oxidative pathways and glucuronidation. Metabolism of lipophilic beta-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 beta-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 beta-blocker pharmacodynamics in terms of beta-blockade. A number of adverse effects of lipophilic beta-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.