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Titolo:
Assessment of CYP2D6 and CY2C19 activity in vivo in humans: A cocktail study with dextromethorphan and chloroguanide alone and in combination
Autore:
Tenneze, L; Verstuyft, C; Becquemont, L; Poirier, JM; Wilkinson, GR; Funck-Brentano, C;
Indirizzi:
St Antoine Univ Hosp, Clin Invest Ctr, Paris, France St Antoine Univ HospParis France Hosp, Clin Invest Ctr, Paris, France St Antoine Univ Hosp, Dept Pharmacol, Paris, France St Antoine Univ Hosp Paris France v Hosp, Dept Pharmacol, Paris, France Ambroise Pare Univ Hosp, Lab Toxicol & Clin Pharmacokinet, Boulogne, France Ambroise Pare Univ Hosp Boulogne France Pharmacokinet, Boulogne, France Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA Vanderbilt Univ Nashville TN USA 37212 Pharmacol, Nashville, TN 37212 USA
Titolo Testata:
CLINICAL PHARMACOLOGY & THERAPEUTICS
fascicolo: 6, volume: 66, anno: 1999,
pagine: 582 - 588
SICI:
0009-9236(199912)66:6<582:AOCACA>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
PERFORMANCE LIQUID-CHROMATOGRAPHY; S-MEPHENYTOIN; IN-VIVO; CYTOCHROME-P450 3A4/5; PROGUANIL METABOLISM; DRUG-METABOLISM; R-MEPHENYTOIN; HUMAN-PLASMA; POLYMORPHISM; OXIDATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
22
Recensione:
Indirizzi per estratti:
Indirizzo: Funck-Brentano, C Hop St Antoine, Ctr Invest Clin, 184 Rue Faubourg St Antoine, F-75012 Paris, France Hop St Antoine 184 Rue Faubourg St Antoine Paris France F-75012
Citazione:
L. Tenneze et al., "Assessment of CYP2D6 and CY2C19 activity in vivo in humans: A cocktail study with dextromethorphan and chloroguanide alone and in combination", CLIN PHARM, 66(6), 1999, pp. 582-588

Abstract

Objectives: Dextromethorphan and chloroguanide (INN, proguanil) are used as prototypic phenotyping substrates of polymorphically expressed CYP2D6 andCYP2C19 in humans. We determined whether the dextromethorphan/dextrorphan and chloroguanide/cycloguanil metabolic ratios, obtained after administration of the parent drugs either alone or in combination, are equivalent. Methods: Thirty-six healthy male volunteers received single oral doses of 80 mg dextromethorphan and 200 mg chloroguanide during a three-period, randomized crossover study. Plasma and urine were collected to calculate metabolic ratios and analyze the disposition kinetics of the probe drugs,Results: ALL subjects were extensive metabolizers for both CYP2D6 and CYP2C19, Chloroguanide kinetics and urinary metabolic ratio were not altered after dextromethorphan administration. Dextromethorphan urinary metabolic ratio increased from -2.52 +/- 0.67 to -2.03 +/- 0.58 (P < .001) in the presence of chloroguanide, This was caused by an increase of dextromethorphan without a significant change of dextrorphan in both urine and plasma, Inhibition of CYP3A-dependent biotransformation of dextromethorphan to methoxymorphinan did not appear to be responsible for this change because the log(dextromethorphan/methoxymorphinan) urinary ratio, an index of CYP3A activity, did not significantly change during chloroguanide coadministration, The chloroguanide and dextromethorphan metabolic ratio determined from urine collection correlated with the corresponding metabolic ratio determined from plasma obtained 3 hours after oral administration,Conclusion: When CYP2D6 and CYP2C19 activity are assessed, dextromethorphan and chloroguanide cannot be associated in a cocktail because chloroguanide increases the dextromethorphan metabolic ratio. CYP2D6 and CPP2C19 activity can be determined from a blood sample drawn 3 hours after oral administration of dextromethorphan and chloroguanide, respectively.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/01/20 alle ore 16:15:43