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Titolo:
Involvement of CYP2D6 activity in the N-oxidation of procainamide in man
Autore:
Lessard, E; Hamelin, BA; Labbe, L; OHara, G; Belanger, PM; Turgeon, J;
Indirizzi:
Hop Laval, Res Ctr, Quebec Heart Inst, St Foy, PQ G1V 4G5, Canada Hop Laval St Foy PQ Canada G1V 4G5 Heart Inst, St Foy, PQ G1V 4G5, Canada Univ Laval, Fac Pharm, St Foy, PQ G1K 7P4, Canada Univ Laval St Foy PQ Canada G1K 7P4 Fac Pharm, St Foy, PQ G1K 7P4, Canada Univ Laval, Fac Med, St Foy, PQ G1K 7P4, Canada Univ Laval St Foy PQ Canada G1K 7P4 , Fac Med, St Foy, PQ G1K 7P4, Canada
Titolo Testata:
PHARMACOGENETICS
fascicolo: 6, volume: 9, anno: 1999,
pagine: 683 - 696
SICI:
0960-314X(199912)9:6<683:IOCAIT>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-LIVER MICROSOMES; LOW-DOSE QUINIDINE; POOR METABOLIZERS; SPARTEINE OXIDATION; EXTENSIVE METABOLIZERS; COMPETITIVE-INHIBITION; LIQUID-CHROMATOGRAPHY; PLASMA-CONCENTRATIONS; GENETIC-POLYMORPHISM; ACETYLATOR PHENOTYPE;
Keywords:
procainamide; CYP2D6; N-oxidation; cytochrome P450;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
65
Recensione:
Indirizzi per estratti:
Indirizzo: Turgeon, J Hop Laval, Res Ctr, Quebec Heart Inst, 2725 Chemin St Foy, St Foy, PQ G1V 4G5, Canada Hop Laval 2725 Chemin St Foy St Foy PQ Canada G1V 4G5 5, Canada
Citazione:
E. Lessard et al., "Involvement of CYP2D6 activity in the N-oxidation of procainamide in man", PHARMACOGEN, 9(6), 1999, pp. 683-696

Abstract

Occurrence of a lupus-like syndrome in a significant number of patients treated with procainamide has limited the clinical use of this antiarrhythmicdrug. 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 andurine 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 Hot 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 demonstratewhether a low CYP2D6 activity, either genetically determined or pharmacologically modulated, could prevent drug-induced lupus erythematosus syndrome observed during chronic therapy with procainamide. Pharmacogenetics 9:683-696 (C) 1999 Lippincott Williams & Wilkins.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 27/01/20 alle ore 16:55:11