title: Polymorphic metabolism of beta-adrenoceptor antagonists.
abstract: Most beta-adrenoceptor blockers undergo extensive oxidative metabolism. The evidence for polymorphism of the debrisoquine type is reviewed. The AUC and half-life of metoprolol were considerably greater in poor metabolisers (PM) of debrisoquine than in extensive metabolisers (EM). Metoprolol alpha-hydroxylation is impaired and O-dealkylation must also be affected. Polymorphism in the former route has been demonstrated in a population of 143 patients to be directly related to debrisoquine phenotype. Bufuralol AUC and half-life are much higher in PM than EM subjects. Hydroxylation at the 1 and 4 positions are affected. Genetic polymorphism for 1-hydroxylation has been shown in family and population studies. Propranolol 4-hydroxylation is defective in PM subjects of debrisoquine but propranolol AUC is not related to phenotype, presumably because other major pathways are unaffected. Oxidation phenotype correlates well with intensity and duration of beta-adrenoceptor blockade after metoprolol, PM subjects requiring only once-daily dosing. However, in EM subjects twice-daily dosing is required even if slow release preparations are used, since plasma metoprolol concentrations may remain negligible 24 h after dosing. The beta-adrenoceptor blocking effects of propranolol and bufuralol are unlikely to be influenced by oxidation status. Anecdotal reports of toxicity arising in PM subjects taking metoprolol or propranolol need to be substantiated. However, vomiting after the administration of bufuralol often occurs in poor metabolisers. Metabolic interactions with drugs sharing the same enzyme system are discussed. Debrisoquine and bufuralol competitively inhibit each other's metabolism in vitro. (ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000009:adverse effects / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D001711:Biotransformation; D004347:Drug Interactions; D004983:Ethanolamines / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008790:Metoprolol / Q000378:metabolism; D011433:Propranolol / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; C010831:bufuralol; D011433:Propranolol; D008790:Metoprolol