Biomaterial Database

Inducing effect of phenobarbital on clozapine metabolism in patients with chronic schizophrenia. 1998

G Facciolà, and A Avenoso, and E Spina, and E Perucca

Institute of Pharmacology, University of Messina, Italy.

The steady state plasma concentrations of clozapine and its two major metabolites, norclozapine and clozapine N-oxide, were compared in patients with schizophrenia treated with clozapine in combination with phenobarbital (n=7), and in control patients treated with clozapine alone (n=15). Patients were matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with phenobarbital had significantly lower plasma clozapine levels than those of the controls (232+/-104 versus 356+/-138 ng/ml; mean, SD, p < 0.05). Plasma norclozapine levels did not differ between the two groups (195+/-91 versus 172+/-61 ng/ml, NS), whereas clozapine N-oxide levels were significantly higher in the phenobarbital group (115+/-49 versus 53+/-31 ng/ml, p < 0.01). Norclozapine/clozapine and clozapine N-oxide/ clozapine ratios were also significantly higher (p < 0.001) in patients comedicated with phenobarbital. These findings suggest that phenobarbital stimulates the metabolism of clozapine, probably by inducing its N-oxidation and demethylation pathways.

UI	MeSH Term	Description	Entries
D008297	Male		Males
D008875	Middle Aged	An adult aged 45 - 64 years.	Middle Age
D010634	Phenobarbital	A barbituric acid derivative that acts as a nonselective central nervous system depressant. It potentiates GAMMA-AMINOBUTYRIC ACID action on GABA-A RECEPTORS, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations.	Phenemal,Phenobarbitone,Phenylbarbital,Gardenal,Hysteps,Luminal,Phenobarbital Sodium,Phenobarbital, Monosodium Salt,Phenylethylbarbituric Acid,Acid, Phenylethylbarbituric,Monosodium Salt Phenobarbital,Sodium, Phenobarbital
D003024	Clozapine	A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent.	Clozaril,Leponex
D003577	Cytochrome P-450 Enzyme System	A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism.	Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D004347	Drug Interactions	The action of a drug that may affect the activity, metabolism, or toxicity of another drug.	Drug Interaction,Interaction, Drug,Interactions, Drug
D004790	Enzyme Induction	An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis.	Induction, Enzyme
D005260	Female		Females
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000328	Adult	A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available.	Adults