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Titolo:
Effect of gender, sex hormones, time variables and physiological urinary pH on apparent CYP2D6 activity as assessed by metabolic ratios of marker substrates
Autore:
Labbe, L; Sirois, C; Pilote, S; Arseneault, M; Robitaille, NM; Turgeon, J; Hamelin, BA;
Indirizzi:
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 Laval Hosp, Quebec Heart Inst, St Foy, PQ, Canada Laval Hosp St Foy PQ Canada Hosp, Quebec Heart Inst, St Foy, PQ, Canada
Titolo Testata:
PHARMACOGENETICS
fascicolo: 5, volume: 10, anno: 2000,
pagine: 425 - 438
SICI:
0960-314X(200007)10:5<425:EOGSHT>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
PERFORMANCE LIQUID-CHROMATOGRAPHY; GROWTH-HORMONE; MENSTRUAL-CYCLE; STEREOSELECTIVE METABOLISM; DRUG-METABOLISM; IN-VIVO; MONOSODIUM GLUTAMATE; OXIDATION PHENOTYPE; LIVER-MICROSOMES; O-DEMETHYLATION;
Keywords:
gender; menstrual cycle; sex hormones; pH; CYP2D6 activity; dextromethorphan : dextrorphan metabolic ratio; metoprolol : alpha-hydroxymetoprolol metabolic ratio;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
60
Recensione:
Indirizzi per estratti:
Indirizzo: Hamelin, BA Biochem Pharma Inc, 275 Armand Frappier Boul, Laval, PQ H7V 4A7, Canada Biochem Pharma Inc 275 Armand Frappier Boul Laval PQ Canada H7V 4A7
Citazione:
L. Labbe et al., "Effect of gender, sex hormones, time variables and physiological urinary pH on apparent CYP2D6 activity as assessed by metabolic ratios of marker substrates", PHARMACOGEN, 10(5), 2000, pp. 425-438

Abstract

The effects of gender, time variables, menstrual cycle phases, plasma sex hormone concentrations and physiologic urinary pH on CYP2D6 phenotyping were studied using two widely employed CYP2D6 probe drugs, namely dextromethorphan and metoprolol. Phenotyping on a single occasion of 150 young, healthy, drug-free women and men revealed that the dextromethorphan: dextrorphan metabolic ratio (MR) was significantly lower (P < 0.0001) in 56 female extensive metabolizers (0.008 +/- 0.021) compared to 86 male extensive metabolizers (0.020 +/- 0.040). Urinary pH was a significant predictor of dextromethorphan: dextrorphan MRs in men and women (P < 0.001). Once-a-month phenotyping with dextromethorphan of 12 healthy young men (eight extensive metabolizers and four poor metabolizers) over a 1-year period, as well as every-other-day phenotyping with dextromethorphan of healthy, pre-menopausal women (10 extensive metabolizers and 2 poor metabolizers) during a complete menstrual cycle, did not follow a particular pattern and showed similar intrasubject variability ranging from 24.1% to 74.5% (mean 50.9%) in men and from 20.5% to 96.2% (mean 52.0%) in women, independent of the CYP2D6 phenotype (P = 0.342). Using metoprolol as a probe drug, considerable intrasubject variability (38.6 +/- 12.0%) but no correlation between metoprolol: alpha-hydroxymetoprolol MRs and pre-ovulatory, ovulatory and luteal phases (mean +/- SDmetoprolol: a-hydroxymetoprolol MRs: 1.086 +/- 1.137 pre-ovulatory; 1.159 /- 1.158 ovulatory and 1.002 +/- 1.405 luteal phase; P > 0.9) or 17 beta-oestradiol, progesterone or testosterone plasma concentrations was observed. There was a significant inverse relationship between physiologic urinary pH and sequential dextromethorphan: dextrorphan MRs as well as metoprolol: alpha-hydroxymetoprolol MRs in men and women, with metabolic ratios varying up to six-fold with metoprolol and up to 20-fold with dextromethorphan (ANCOVA P < 0.001). We conclude that apparent CYP2D6 activity is highly variable, independent of menstrual cycle phases, sex hormones, time variables or phenotype. Up to 80% of the observed variability can be explained by variations of urinary pH within the physiological range. An apparent phenotype shift as a result of variations in urinary pH may be observed in individuals who have metabolic ratios close to the population antimode. Pharmacogenetics10:425-438 (C) 2000 Lippincott Williams & Wilkins.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/05/20 alle ore 23:17:30