Involvement of CYP2D6 activity in the N-oxidation of procainamide in man

Occurrence of a lupus-like syndrome in a significant number of patients tre ated with procainamide has limited the clinical use of this antiarrhythmic drug. In-vitro studies conducted in our laboratory have demonstrated that C YP2D6 is the major cytochrome P450 isozyme involved in the formation of N-h ydroxyprocainamide, a metabolite potentially involved in the drug-induced l upus erythematosus syndrome observed with procainamide. in the current stud y, we evaluated the role of CYP2D6 activity in the in-vivo oxidation of pro cainamide in man, Nineteen healthy individuals, 13 with high (extensive met abolizers) and six with low (poor metabolizers) CYP2D6 activity, received a single 500 mg oral dose of procainamide hydrochloride on two occasions, on ce alone (period 1) and once during the concomitant administration of the s elective inhibitor quinidine (50 mg four times daily; period 2), Blood and urine samples were collected over 36 h after drug administration of procain amide and analysed for procainamide and its major metabolites (N-acetylproc ainamide, desethylprocainamide, N-acetyl-desethylprocainamide, p-aminobenzo ic acid and its N-acetylated derivative, and nitroprocainamide), No differe nces were observed in the oral and renal clearances of procainamide between extensive metabolizers and poor metabolizers during either study period. H owever, partial metabolic clearance of procainamide to desethylprocainamide was significantly greater in extensive metabolizers than in poor metaboliz ers during both periods. Most importantly, the urinary excretion of nitropr ocainamide during period 1 was measurable in 7/13 extensive metabolizers bu t in none of the poor metabolizers, During the concomitant administration o f quinidine, nitroprocainamide could Hot be detected in the urine of any in dividuals tested. Therefore, our results suggest that CYP2D6 is involved in the in-vivo aliphatic amine deethylation and N-oxidation of procainamide a t its arylamine function in man, Further studies are needed to demonstrate whether a low CYP2D6 activity, either genetically determined or pharmacolog ically modulated, could prevent drug-induced lupus erythematosus syndrome o bserved during chronic therapy with procainamide. Pharmacogenetics 9:683-69 6 (C) 1999 Lippincott Williams & Wilkins.