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Titolo:
Inhibition of debrisoquine hydroxylation with quinidine in subjects with three or more functional CYP2D6 genes
Autore:
Dalen, P; Dahl, ML; Andersson, K; Bertilsson, L;
Indirizzi:
Huddinge Univ Hosp, Karolinska Inst, Dept Med Lab Sci & Technol, Div Clin Pharmacol, Huddinge, Sweden Huddinge Univ Hosp Huddinge Sweden Div Clin Pharmacol, Huddinge, Sweden
Titolo Testata:
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 2, volume: 49, anno: 2000,
pagine: 180 - 184
SICI:
0306-5251(200002)49:2<180:IODHWQ>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
SPARTEINE OXIDATION POLYMORPHISM; POOR METABOLIZERS; SWEDISH POPULATION; HUMAN-LIVER; PHARMACOKINETICS; AMPLIFICATION; DUPLICATION; GENOTYPES; VERAPAMIL; PLASMA;
Keywords:
CYP2D6; cytochrome P450; debrisoquine; gene amplification; gene duplication; genotype; phenotype; quinidine;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
34
Recensione:
Indirizzi per estratti:
Indirizzo: Dahl, ML Huddinge Univ Hosp C168, Dept Clin Pharmacol, S-14186 Huddinge, Sweden Huddinge Univ Hosp C168 Huddinge Sweden S-14186 uddinge, Sweden
Citazione:
P. Dalen et al., "Inhibition of debrisoquine hydroxylation with quinidine in subjects with three or more functional CYP2D6 genes", BR J CL PH, 49(2), 2000, pp. 180-184

Abstract

Aims To study whether the CYP2D6 capacity in ultrarapid metabolizers of debrisoquine due to duplication/multiduplication of a functional CYP2D6 gene,can be 'normalised' by low doses of the CYP2D6 inhibitor quinidine and whether this is dose-dependent. Methods Five ultrarapid metabolizers of debrisoquine with 3, 4 or 13 functional CYP2D6 genes were given single oral doses of 5, 10, 20, 40, 80 and 160 mg quinidine. Four hours after quinidine intake, 10 mg debrisoquine was given. Urine was collected for 6 h after debrisoquine administration. Debrisoquine and its 4-hydroxymetabolite were analysed by h.p.l.c. and the debrisoquine metabolic ratio (MR) was calculated. Results Without quinidine the MR in the ultrarapid metabolizers ranged between 0.01 and 0.07. A dose-effect relationship could be established for quinidine with regard to the inhibitory effect on CYP2D6 activity. To reach anMR of 1-2, subjects with 3 or 4 functional genes required a quinidine doseof about 40 mg, while the sister and brother with 13 functional genes required about 80 mg quinidine. After 160 mg quinidine, the MRs, in the subjects with 3, 3, 4, 13 and 13 functional genes, were 12.6, 10.1, 9.2, 2.4 and 2.2, respectively. Conclusions A dose-effect relationship could be established for quinidine inhibition of CYP2D6 in ultrarapid metabolizers. The clinical use of low doses of quinidine as an inhibitor of CYP2D6 might be considered in ultrarapid metabolizers taking CYP2D6 metabolized drugs rather than giving increaseddoses of the drug. Normalizing the metabolic capacity of CYP2D6, by givinga low dose of quinidine, may solve the problem of 'treatment resistance' caused by ultrarapid metabolism.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 27/01/20 alle ore 13:55:22