Electrochemical determination of N-oxidized procainamide metabolites and functional assessment of effects on murine cells in vitro.
Because of the implication of N-oxidized metabolites of procainamide in the induction of drug-related lupus, we have studied the electrochemical behavior of these metabolites and developed an electrochemical synthesis of nitrosoprocainamide. This synthesis was developed using procainamide hydroxylamine as the starting material which was oxidized to the nitroso species at an applied potential of 700 mV vs Ag/AgCl using a carbon packed bed bulk electrolysis flow cell. Conversion efficiencies of greater than 95% were achieved with this method. Subsequent studies with a chemically diverse series of biocompounds were used to investigate possible reactions between the procainamide hydroxylamine and nitroso species and these selected molecules. Only antioxidants such as cysteine, glutathione and ascorbic acid were found to react with the nitroso compound as determined by electrochemical methods, and this reaction was characterized as primarily a simple redox reaction at physiological pH. Animal studies conducted with murine spleen cells incubated with mitogens and various procainamide compounds demonstrated that the N-oxidized metabolites are the active immunopharmacologic agents.
Wheeler
J F
JF
Biomedical Chemistry Research Center, Department of Chemistry, Cincinnati, OH 45221.
Lunte
C E
CE
Heineman
W R
WR
Adams
L
L
Hess
E V
EV
D000120:Acecainide / Q000494:pharmacology; D000818:Animals; D001205:Ascorbic Acid; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D003545:Cysteine; D004247:DNA / Q000096:biosynthesis; D004563:Electrochemistry; D004572:Electrolysis; D005978:Glutathione; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D051379:Mice; D010084:Oxidation-Reduction; D011342:Procainamide / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D013053:Spectrophotometry; D013154:Spleen / Q000187:drug effects* / Q000378:metabolism
D004247:DNA; D000120:Acecainide; C051948:procainamide 4-hydroxylamine; C056538:4-nitrosoprocainamide; D005978:Glutathione; D003545:Cysteine; D011342:Procainamide; D001205:Ascorbic Acid