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Occurrence of a lupus-like syndrome in a significant number of patients treated with procainamide has limited the clinical use of this antiarrhythmic drug. In-vitro studies conducted in our laboratory have demonstrated that CYP2D6 is the major cytochrome P450 isozyme involved in the formation of N-hydroxyprocainamide, a metabolite potentially involved in the drug-induced lupus erythematosus syndrome observed with procainamide. In the current study, we evaluated the role of CYP2D6 activity in the in-vivo oxidation of procainamide in man. Nineteen healthy individuals, 13 with high (extensive metabolizers) and six with low (poor metabolizers) CYP2D6 activity, received a single 500 mg oral dose of procainamide hydrochloride on two occasions, once alone (period 1) and once during the concomitant administration of the selective inhibitor quinidine (50 mg four times daily; period 2). Blood and urine samples were collected over 36 h after drug administration of procainamide and analysed for procainamide and its major metabolites (N-acetylprocainamide, desethylprocainamide. N-acetyl-desethylprocainamide, p-aminobenzoic acid and its N-acetylated derivative, and nitroprocainamide). No differences were observed in the oral and renal clearances of procainamide between extensive metabolizers and poor metabolizers during either study period. However, partial metabolic clearance of procainamide to desethylprocainamide was significantly greater in extensive metabolizers than in poor metabolizers during both periods. Most importantly, the urinary excretion of nitroprocainamide during period 1 was measurable in 7/13 extensive metabolizers but in none of the poor metabolizers. During the concomitant administration of quinidine, nitroprocainamide could not be detected in the urine of any individuals tested. Therefore, our results suggest that CYP2D6 is involved in the in-vivo aliphatic amine deethylation and N-oxidation of procainamide at its arylamine function in man. Further studies are needed to demonstrate whether a low CYP2D6 activity, either genetically determined or pharmacologically modulated, could prevent drug-induced lupus erythematosus syndrome observed during chronic therapy with procainamide.