ISSN:
1432-1041
Keywords:
β-Blockers
;
debrisoquine metabolism
;
extensive metabolizers
;
genetic polymorphism
;
poor metabolizers
;
glucuronidation
;
lipophilicity
;
pharmacodynamics
;
pharmacokinetics
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
,
Medicine
Notes:
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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00543715
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