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Titolo:
Clozapine pharmacokinetics and pharmacodynamics studied with CYP1A2-null mice
Autore:
Aitchison, KJ; Jann, MW; Zhao, JH; Sakai, T; Zaher, H; Wolff, K; Collier, DA; Kerwin, RW; Gonzalez, FJ;
Indirizzi:
Inst Psychiat, Clin Pharmacol Sect, London SE5 8AF, England Inst PsychiatLondon England SE5 8AF macol Sect, London SE5 8AF, England Inst Psychiat, Sect Genet Epidemiol & Biostat, London SE5 8AF, England Inst Psychiat London England SE5 8AF & Biostat, London SE5 8AF, England Mercer Univ Pharm Practice, Atlanta, GA USA Mercer Univ Pharm Practice Atlanta GA USA harm Practice, Atlanta, GA USA NCI, Lab Metab, NIH, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892NCI, Lab Metab, NIH, Bethesda, MD 20892 USA Natl Addict Ctr, London, England Natl Addict Ctr London EnglandNatl Addict Ctr, London, England
Titolo Testata:
JOURNAL OF PSYCHOPHARMACOLOGY
fascicolo: 4, volume: 14, anno: 2000,
pagine: 353 - 359
SICI:
0269-8811(2000)14:4<353:CPAPSW>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
REFRACTORY SCHIZOPHRENIC-PATIENTS; INDUCED AGRANULOCYTOSIS; CLINICAL-RESPONSE; PLASMA CLOZAPINE; IN-VITRO; N-DESMETHYLCLOZAPINE; 5'-FLANKING REGION; HUMAN NEUTROPHILS; METABOLISM; PHENOTYPES;
Keywords:
clozapine; CYP1A2; cytochrome P450; knockout; metabolism; pharmacodynamics; pharmacokinetics;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
61
Recensione:
Indirizzi per estratti:
Indirizzo: Aitchison, KJ Inst Psychiat, Clin Pharmacol Sect, 1 Windsor Walk,Denmark Hill, London SE5 8AF, England Inst Psychiat 1 Windsor Walk,Denmark Hill London England SE5 8AF
Citazione:
K.J. Aitchison et al., "Clozapine pharmacokinetics and pharmacodynamics studied with CYP1A2-null mice", J PSYCHOPH, 14(4), 2000, pp. 353-359

Abstract

The aim of this study was to use the CYP1A2-null mouse to investigate the in-vivo contribution of CYP1A2 to clozapine pharmacokinetics and pharmacodynamics. An intraperitoneal injection of 10 mg/kg clozapine was administeredto four male CYP1A2 -/- mice and four male wild-type mice. Clozapine, desmethylclozapine, and clozapine N-oxide concentrations in sequential tail blood samples were measured by HPLC with UV detection. Behavioural parameters were recorded at each time point. The area under the curve (AUC) of clozapine was 2.6 times greater, the clearance of clozapine was 2.6 times slower, and the half-life was 1.2 times longer in the CYP1A2 -/- mice (p = 0.0143) as compared to the wild-type mice. Sixty-one percent of the clozapine clearance in wild-type mice was calculated to be mediated by CYP1A2, The AUC of desmethylclozapine was 1.6 times lower in the CYP1A2 -/- mice compared to the wild-type mice (p = 0.0286), while there was a trend for the AUC of clozapine N-oxide to be greater in the CYP1A2 -/- mice (p = 0.0571). The CYP1A2-/- mice were significantly more drowsy and showed more motor impairment (p = 0.0145) and myoclonus than the wild-type mice. Our results indicate that, in vivo, CYP1A2 is the major determinant of clozapine clearance, contributes significantly to the demethylation of clozapine, and has a negligible contribution to the N-oxidation, Our data also indicate that CYP1A2 poor metabolizers might be more susceptible than extensive metabolizers to dose-related adverse effects of clozapine, such as sedation, myoclonus and seizures.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 21/01/20 alle ore 00:51:27