Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans
Autore:
Lessard, E; Yessine, MA; Hamelin, BA; OHara, G; LeBlanc, J; 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 Robert Giffard Hosp Ctr, St Foy, PQ, Canada Robert Giffard Hosp Ctr St Foy PQ Canada rd Hosp Ctr, St Foy, PQ, Canada
Titolo Testata:
PHARMACOGENETICS
fascicolo: 4, volume: 9, anno: 1999,
pagine: 435 - 443
SICI:
0960-314X(199908)9:4<435:IOCAOT>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
PERFORMANCE LIQUID-CHROMATOGRAPHY; HUMAN-LIVER; GENETIC-POLYMORPHISM; HUMAN-PLASMA; DEBRISOQUINE; SPARTEINE; OXIDATION; ALLELE; DEXTROMETHORPHAN; PHARMACOKINETICS;
Keywords:
venlafaxine; CYP2D6; cytochrome P-450; metabolism;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
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., "Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans", PHARMACOGEN, 9(4), 1999, pp. 435-443

Abstract

According to in-vitro studies with microsomes from human livers and from yeast expression systems with high CYP2D6 activity, the major oxidation pathway of venlafaxine is catalysed by CYP2D6, In this study, we investigated the role of the CYP2D6 polymorphism and the effects of low-dose quinidine, aselective inhibitor of CYP2D6, on the disposition of venlafaxine, Fourteenhealthy men, eight with the extensive metabolizer and six with the poor metabolizer phenotype were administered venlafaxine hydrochloride 18.75 mg orally every 12 h for 48 h on two occasions (1 week apart); once done and once during the concomitant administration of quinidine sulfate 100 mg every 12 h, Blood and urine samples were collected under steady-state conditions over one dosing interval (12 h), When venlafaxine was administered alone, the oral clearance of venlafaxine was more than fourfold less in poor metabolizers compared to extensive metabolizers (P < 0.05), This was mainly due toa decreased capability of poor metabolizers to form O-desmethylated metabolites at the position 4 of the aromatic moiety, In extensive metabolizers, quinidine decreased venlafaxine oral clearance from 100 +/- 62 l/h to 17 +/- 5 l/h (mean +/- SD; P < 0.05) without any effects on renal clearance (4 +/- 1 l/h during venlafaxine alone and 4 +/- 1 l/h during venlafaxine plus quinidine). In these individuals, the sequential metabolism of venlafaxine to O-desmethylvenlafaxine and to N,O-didesmethylvenlafaxine was inhibited byquinidine coadministration so that metabolic clearances to O-desmethylatedmetabolites decreased from 43 +/- 32 l/h to 2 +/- 1 l/h (P < 0.05). In poor metabolizers, coadministration of quinidine did not cause significant changes in oral clearance and partial metabolic clearances of venlafaxine to its various metabolites. Decreased CYP2D6 activity could also be associated with cardiovascular toxicity as observed in four patients during treatment with the drug. Thus, genetically determined or pharmacologically altered CYP2D6 activity represents a major determinant of venlafaxine disposition in humans. Pharmacogenetics 9:435-443 (C) 1999 Lippincott Williams & Wilkins.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/01/20 alle ore 04:38:57