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Titolo:
Intraindividual variability in male hepatic CYP3A4 activity assessed by alfentanil and midazolam clearance
Autore:
Kharasch, ED; Jubert, C; Senn, T; Bowdle, TA; Thummel, KE;
Indirizzi:
Univ Washington, Dept Anesthesiol, Seattle, WA 98195 USA Univ Washington Seattle WA USA 98195 t Anesthesiol, Seattle, WA 98195 USA Univ Washington, Dept Med Chem, Seattle, WA 98195 USA Univ Washington Seattle WA USA 98195 Dept Med Chem, Seattle, WA 98195 USA Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA Univ Washington Seattle WA USA 98195 pt Pharmaceut, Seattle, WA 98195 USA Puget Sound Vet Affairs Hlth Care Syst, Anesthesiol Serv, Seattle, WA USA Puget Sound Vet Affairs Hlth Care Syst Seattle WA USA v, Seattle, WA USA
Titolo Testata:
JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 7, volume: 39, anno: 1999,
pagine: 664 - 669
SICI:
0091-2700(199907)39:7<664:IVIMHC>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
MENSTRUAL-CYCLE PHASE; CYTOCHROME-P450 3A4; METABOLISM; PHARMACOKINETICS; GENDER; ELIMINATION; HUMANS; PROBE; AGE; PHARMACODYNAMICS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
36
Recensione:
Indirizzi per estratti:
Indirizzo: Kharasch, ED Univ Washington, Dept Anesthesiol, Box 356540, Seattle, WA 98195 USA Univ Washington Box 356540 Seattle WA USA 98195 WA 98195 USA
Citazione:
E.D. Kharasch et al., "Intraindividual variability in male hepatic CYP3A4 activity assessed by alfentanil and midazolam clearance", J CLIN PHAR, 39(7), 1999, pp. 664-669

Abstract

Clinical investigations using isoform-selective probes to phenotype cytochrome P450 activity and interaction studies using isoform-selective inhibitors to determine P450 involvement in drug metabolism assume minimal interdayvariability in P450 activity. CYP3A4 is the most abundant human P450 isoform and metabolizes approximately half of all therapeutic agents. This investigation evaluated interday variability in hepatic CYP3A4 activity in males, using the clearances of midazolam and alfentanil as metabolic probes. Midazolam (1 mg) followed 1 hour later by alfentanil (20 mu g/kg) were administered by in tra venous bolus to 9 nonsmoking male volunteers (ages 30 +/- 8years). Drug administration was repeated 12 and 20 days later. Venous plasma midazolam and alfentanil concentrations were determined by gas chromatography/mass spectrometry. Drug clearances were determined by noncompartmental and multiexponential analysis. There were no significant interday differences in plasma drug concentrations or clearances (3.9 +/- 1.4, 3.9 +/- 1.7,and 4.2 +/- 1.7 ml/kg/min for alfentanil, respectively, and 6.6 +/- 2.0, 7.9 +/- 2.4, and 7.9 +/- 2.5 ml/kg/min for midazolam, respectively, on days 1, 13, and 21 [mean +/- SD]). Interday variability in clearance was 13 % +/- 6% and 1 9 % +/- 12 % for alfentanil and midazolam, respectively. Interday variability in the clearance of these probes, and presumably hepatic CYP3A4 activity, was small compared with interindividual variability Consideration of interday variability in the hepa tic metabolism of CYP3A4 substratesdoes not appear significant in the design of clinical trials. (C) 1999 theAmerican College of Clinical Pharmacology.

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Documento generato il 18/01/20 alle ore 22:18:41