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Steady‐state serum levels of quinidine and active metabolites in cardiac patients with varying degrees of renal function
Author(s) -
Drayer Dennis E.,
Lowenthal David T.,
Restivo Kathleen M.,
Schwartz Allan,
Cook Clarence E.,
Reidenberg Marcus M.
Publication year - 1978
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt197824131
Subject(s) - quinidine , metabolite , active metabolite , pharmacology , chemistry , urine , medicine
The concentrations of quinidine, (3S)‐3‐hydroxyquinidine (3‐0H), and 2′‐oxoquinidinone (2′‐OXO) in serum samples from 25 patients on long‐term quinidine therapy were determined by a high‐pressure liquid chromatography assay. Large individual variation in the levels of each of the compounds measured was observed. After correcting for differences in protein binding, the ratio of 3‐OH/quinidine in serum water is 0.61 ± 0.31 (SD) and the ratio of 2′‐OXO/quinidine is 0.39 ± 0.44. Seven of the 25 patients had serum water levels of one of these metabolites similar to or greater than that of quinidine. The quinidine levels, after normalizing for dose, are significantly higher in hemodialysis patients (about twice) than in nonazotemic patients; azotemic patients have mean values intermediate between them. Quinidine, 3‐OH, and 2′‐OXO are equally potent antiarrhythmic drugs (ED 50 = 0.18,0.17, and 0.21 mmoles/kg, respectively) when tested against chloroform‐ and hypoxia‐induced ventricular fibrillation in mice. O‐Desmethylquinidine, a new metabolite detected in urine of quinidine‐treated patients, is less active. Quinidine and vOXO are equally potent (ED 50 = 0.010 mmoles/kg), while 3‐OH seems less potent and more toxic when tested against BaCl 2 ‐induced ventricular arrhythmias in rabbits. Thus, these metabolites appear to contribute to the effects of quinidine and may make a significant contribution in some cases.