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.
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D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D003647:Debrisoquin / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008055:Lipids; D008790:Metoprolol / Q000494:pharmacology; D010641:Phenotype; D011110:Polymorphism, Genetic; D011433:Propranolol / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D013999:Timolol / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D005965:Glucuronates; D008055:Lipids; D013999:Timolol; C010831:bufuralol; D011433:Propranolol; D008790:Metoprolol; D003647:Debrisoquin