Biomedical subjects
Publications and source records attributed to L K Pershing.
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1. By several criteria, macrolide antibiotics constitute a new class of nitrogenous cytochrome P-450 metabolic-intermediate complex-forming compounds. 2. Macrolide antibiotic metabolic-intermediate complexes are only formed in livers induced with phenobarbital or with the macrolide antibiotics themselves. The extent of metabolic-intermediate complex formation in microsomes from phenobarbital-induced rats is lower than that seen for members of the amphetamine and SKF 525-A classes of compounds. 3. Cytochrome P-450 induced by macrolide antibiotics, of which troleandomycin is the most potent, is extensively sequestered as a metabolic intermediate complex in vivo. 4. Cytochrome P-450 induced by troleandomycin differs, using several criteria, from those induced by phenobarbital, beta-naphthoflavone or SKF 525-A, and those present in uninduced rats.
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Two different chronic dosing regimens of quinidine gluconate were administered to each of four healthy volunteers in a pilot study to evaluate quinidine for nonlinear pharmacokinetics. Analysis of plasma quinidine levels following the last dose indicates that disproportionate increases in steady-state plasma concentrations can occur in some subjects as the daily dose increases. Measurement of 2'-oxoquinidinone (2'-OXO) and 3-hydroxyquinidine (3-OH) metabolites revealed that the formation of 2'-OXO is proportional to the availability of quinidine base. Hydroxylation was a more variable process. Rate-limited hydroxylation was documented in one subject, and an apparent increase in hepatic microsomal enzyme-mediated hydroxylation was shown in a second subject who ingested large amounts of caffeine daily. By using a highly selective high-performance liquid chromatography assay technique, the total body clearance of quinidine was found to be greater than previously published data. Our results suggest that some individuals may exhibit dose-dependent elimination of quinidine and that the variability in quinidine's pharmacokinetics is related in part to its hydroxylation. Future studies must use highly specific quinidine assays and control for variables that may influence this route of metabolism.
A rapid and simple method is described for the separation of quinidine (Q), its metabolites 3-hydroxyquinidine (30HQ) and 2'oxoquinidinone (QD) as well as the quinidine salt contaminant, dihydroquinidine (DHQ) in plasma by high pressure liquid chromatography (HPLC). A silica column was used with methanol: 1 N ammonium nitrate: 2 N ammonium hydroxide (28:1:1 v/v) as the mobile phase to separate the compounds and a fluorescence spectrophotometer for detection. Application of this method is demonstrated by the analysis of human plasma samples collected from a volunteer during a phenytoin-quinidine drug interaction study.
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