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Titolo:
Disposition of debrisoquine in Caucasians with different CYP2D6-genotypes including those with multiple genes
Autore:
Dalen, P; Dahl, ML; Eichelbaum, M; Bertilsson, L; Wilkinson, GR;
Indirizzi:
Huddinge Univ Hosp, Karolinska Inst, Div Clin Pharmacol, Dept Med Lab Sci & Technol, S-14186 Huddinge, Sweden Huddinge Univ Hosp Huddinge Sweden S-14186 nol, S-14186 Huddinge, Sweden Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-7000 Stuttgart, Germany Dr Margarete Fischer Bosch Inst Clin Pharmacol Stuttgart Germany D-7000 Vanderbilt Univ, Div Clin Pharmacol, Nashville, TN USA Vanderbilt Univ Nashville TN USA , Div Clin Pharmacol, Nashville, TN USA
Titolo Testata:
PHARMACOGENETICS
fascicolo: 6, volume: 9, anno: 1999,
pagine: 697 - 706
SICI:
0960-314X(199912)9:6<697:DODICW>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
POLYMORPHIC DRUG OXIDATION; POOR METABOLIZER PHENOTYPE; CYP2D6 GENE; CYTOCHROME-P450 2D6; SWEDISH POPULATION; HYDROXYLATION; SPARTEINE; ALLELE; 4-HYDROXYLATION; AMPLIFICATION;
Keywords:
cytochrome P450; CYP2D6; debrisoquine; genotype; phenotype; gene duplication; gene amplification;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Dalen, P Huddinge Univ Hosp, Dept Clin Pharmacol, S-14186 Huddinge, SwedenHuddinge Univ Hosp Huddinge Sweden S-14186 186 Huddinge, Sweden
Citazione:
P. Dalen et al., "Disposition of debrisoquine in Caucasians with different CYP2D6-genotypes including those with multiple genes", PHARMACOGEN, 9(6), 1999, pp. 697-706

Abstract

Debrisoquine is a major prototypic in-vivo probe used to assess polymorphic CYP2D6 activity in humans, based on the 0-8 h urinary excretion of unchanged drug and its 4-hydroxy metabolite (the so-called metabolic ratio). The primary purpose of the study was to investigate further the relationship between genotype and phenotype by determining the overall disposition characteristics of the drug in selected groups of healthy Swedish Caucasian individuals. Debrisoquine (20 mg) was orally administered to five poor metabolizers with no functional CYP2D6 gene, five heterozygous extensive metabolizers, five homozygous extensive metabolizers, five ultrarapid metabolizers withduplicated/triplicated CYP2D6*2 genes and one individual with 13 copies ofCYP2D6*2. Peak plasma levels of debrisoquine and 4-hydroxydebrisoquine were attained within 2-4 h and then declined in a multi-exponential fashion over 96 h, However, the post 8-h period of the elimination process was characterized by irregular fluctuations that prevented formal pharmacokinetic analysis. Nevertheless, marked differences were apparent in the compounds' plasma level-time profiles between the CYP2D6 genotypes. For example, in the case of debrisoquine, the mean ratio of the AUC(0-8) values was 22:22:7:6:1,corresponding to 0, 1, 2, 3/4 and 13 genes and, for 4-hydroxydebrisoquine,the respective values were 1:7:19:28:17. The 0-96 h urinary recovery of debrisoquine differed 100-fold between the genotypes, being essentially complete in poor metabolizers and zero in the individual with 13 CYP2D6*2 genes.4-hydroxydebrisoquine excretion increased according to the number of functional CYP2D6 genes. A highly significant correlation (r(s) = 0.95, P < 0.001) was observed between the plasma AUC(0-8) ratio for debrisoquine to 4-hydroxydebrisoquine and the 0-8 h urinary metabolic ratio. This study demonstrates that the number of functional CYP2D6 alleles is critically important in the plasma concentration-time curves of debrisoquine and its CYP2D6-mediated 4-hydroxy metabolite. Concentration-related pharmacologic effects wouldbe expected to be similarly affected by gene dosage and it is likely that the same situation also apples to other drugs whose elimination is importantly determined by this enzyme; for example, many antidepressants and neuroleptics, antiarrhythmic agents, beta-adrenoceptor antagonists and opiates. Pharmacogenetics 9:697-706 (C) 1999 Lippincott Williams & Wilkins.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/01/20 alle ore 01:50:44