Interspecies variability and drug interactions of clozapine metabolism by microsomes

BUN, H ; DISDIER, B ; et al.

In: Meeting of the Belgian Society of Fundamental and Clinical Physiology and PharmacologyFundamental & clinical pharmacology 13(5):577-581; Jg. 13 (1999) 5, S. 577-581

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Cytochrome P450 expression in liver is influenced by several factors, including species, sex and strain. We compared metabolism formation of clozapine in different species (rat, mouse, guinea-pig, dog, monkey and man) so as to choose between species to further validate interaction studies. Liver microsomes of male and female Sprague-Dawley rats, hairless rats, OFI mice, Balb C mice and Dunkin-Hartley albino guinea-pigs, male beagle dogs, male cynomolgus monkeys and man were used to investigate in vitro metabolism of clozapine. This process was dependent on the presence of NADPH and on the presence of microsome protein. In addition, we observed the formation of desmethyl- and N-oxide metabolites, with the rate of formation of each of these compounds varying with species, sex and strain of microsomes incubated. The desmethyl- and N-oxide metabolites formed were statistically greater in male than in female rats, mice in the two strains studied, as well as for the guinea-pigs. Levels of desmethyl clozapine formed were high for the rats and no significant difference in clozapine biotransformation was observed between Sprague-Dawley and hairless rats. For man, the formation of metabolites of clozapine was comparable with guinea-pig, dog and monkey. In addition, we screened the effect of 52 molecules, representative of 11 different therapeutic classes, on the metabolism of clozapine by rat liver microsomes. We found that most of the calcium channel blockers (diltiazem, felodipine, isradipine, lacidipine, nicardipine and nitrendipine), antifungals (ketoconazole, miconazole) and two anticancer drugs (paclitaxel, teniposide) caused more than 50% inhibition of clozapine metabolism in vitro. The extent of inhibition was increased in a concentration-dependant manner. Complementary clinical and pharmacokinetic studies should be performed to confirm these results.

Titel:	Interspecies variability and drug interactions of clozapine metabolism by microsomes
Autor/in / Beteiligte Person:	BUN, H ; DISDIER, B ; AUBERT, C ; CATALIN, J
Link:	Full Text Finder (Volltext) E-Journal im Bestand der UB Hagen? View record from PASCAL Archive
Quelle:	Meeting of the Belgian Society of Fundamental and Clinical Physiology and PharmacologyFundamental & clinical pharmacology 13(5):577-581; Jg. 13 (1999) 5, S. 577-581
Veröffentlichung:	Oxford: Blackwell, 1999
Medientyp:	Konferenz
Umfang:	print, 15 ref
ISSN:	0767-3981 (print)
Schlagwort:	Asie Asia Chine China Pharmacology drugs Pharmacologie, galénique Sciences biologiques et medicales Biological and medical sciences Sciences medicales Medical sciences Pharmacologie. Traitements medicamenteux Pharmacology. Drug treatments Neuropharmacologie Neuropharmacology Psycholeptiques: tranquillisant, neuroleptique. Psycholeptics: tranquillizer, neuroleptic. Psychologie. Psychanalyse. Psychiatrie Psychology. Psychoanalysis. Psychiatry Psychopharmacologie Psychopharmacology Enzyme Enzima Mammalia Oxidoreductases Primates Rodentia Vertebrata Appareil digestif Digestive system Aparato digestivo Association médicamenteuse Drug combination Asociación medicamentosa Clozapine Clozapina Cobaye Guinea pig Cobayo Comparaison interspécifique Interspecific comparison Comparación interespecífica Cytochrome P450 Citocromo P450 Drug-metabolizing enzyme Foie Liver Hígado Homme Human Hombre In vitro Interaction médicamenteuse Drug interaction Interacción medicamentosa Modèle animal Animal model Modelo animal Métabolisme Metabolism Metabolismo Neuroleptique Neuroleptic Neuroléptico Psychotrope Psychotropic Psicotropo Rat Rata Singe Monkey Mono Souris Mouse Ratón Unspecific monooxygenase Dibenzodiazépine Subject Geographic: Asie Asia Chine China
Sonstiges:	Nachgewiesen in: PASCAL Archive Sprachen: English Original Material: INIST-CNRS Document Type: Conference Paper File Description: text Language: English Author Affiliations: Department of Pharmacokinetics and Toxicokinetics, Faculty of Pharmacy, Université de la Mediterannée, Marseilles, France Rights: Copyright 1999 INIST-CNRS ; CC BY 4.0 ; Sauf mention contraire ci-dessus, le contenu de cette notice bibliographique peut être utilisé dans le cadre d’une licence CC BY 4.0 Inist-CNRS / Unless otherwise stated above, the content of this bibliographic record may be used under a CC BY 4.0 licence by Inist-CNRS / A menos que se haya señalado antes, el contenido de este registro bibliográfico puede ser utilizado al amparo de una licencia CC BY 4.0 Inist-CNRS Notes: Pharmacological treatments ; Psychopathology. Psychiatry. Clinical psychology ; FRANCIS

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