Competitive inhibition of sparteine oxidation in human liver by beta-adrenoceptor antagonists and other cardiovascular drugs.
The rate of oxidation of sparteine by the 9000 x g supernatant fraction of a human liver was measured in the presence of various drugs which exert cardiovascular effects. Hexamethonium, ouabain, caffeine and isoproterenol had no effect on this rate, while alprenolol, metoprolol, oxprenolol, propranolol, timolol, pindolol, lidocaine, mexiletine, 17-n-pentyl-sparteine, tolazoline, quinine, quinidine, cinchonine and cinchonidine inhibited the in vitro reaction competitively. Stereoselective inhibition was observed between quinine (Ki = 15 microM) and quinidine (Ki = 0.06 microM). Genetic evidence suggests that the primary metabolism of sparteine depends on a single species of cytochrome P450. In vitro competitive inhibition of sparteine oxidation by a drug indicates that this drug is capable of occupying the same enzymatic site as sparteine. This may mean that the competing drug is also metabolized at that site and thereby subject to the same genetic variation as sparteine's oxidation; absence of inhibition excludes this possibility.
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011802:Quinidine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D013034:Sparteine / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D002317:Cardiovascular Agents; D013034:Sparteine; D011803:Quinine; D011802:Quinidine