title: Treatment-resistance to clozapine in association with ultrarapid CYP1A2 activity and the C-->A polymorphism in intron 1 of the CYP1A2 gene: effect of grapefruit juice and low-dose fluvoxamine.
abstract: Antipsychotic response to clozapine varies markedly among patients with schizophrenia. The disposition of clozapine is dependent, in part, on the cytochrome P-450 (CYP) 1A2 enzyme in vivo. In theory, a very high CYP1A2 activity may lead to subtherapeutic concentrations and treatment resistance to clozapine. This prospective case study evaluates the clinical significance of ultrarapid CYP1A2 activity and a recently discovered single nucleotide (C --> A) polymorphism in intron 1 of the CYP1A2 gene (CYP1A2*F) for treatment resistance to clozapine. In addition, we describe the effect of grapefruit juice or low-dose fluvoxamine (25-50 mg/d) coadministration on clozapine and active metabolite norclozapine steady-state plasma concentration and antipsychotic response.
authors.affiliation: Department of Pharmacology, University of Toronto, Ontario, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Ozdemir
authors.forename: W
authors.initials: W
authors.lastname: Kalow
authors.forename: A B
authors.initials: AB
authors.lastname: Okey
authors.forename: M S
authors.initials: MS
authors.lastname: Lam
authors.forename: L J
authors.initials: LJ
authors.lastname: Albers
authors.forename: C
authors.initials: C
authors.lastname: Reist
authors.forename: J
authors.initials: J
authors.lastname: Fourie
authors.forename: P
authors.initials: P
authors.lastname: Posner
authors.forename: E J
authors.initials: EJ
authors.lastname: Collins
authors.forename: R
authors.initials: R
authors.lastname: Roy
mesh_terms: D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage; D014150:Antipsychotic Agents / Q000097:blood / Q000627:therapeutic use; D001628:Beverages; D002957:Citrus / Q000201:enzymology; D003024:Clozapine / Q000097:blood / Q000627:therapeutic use*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics* / Q000378:metabolism*; D016666:Fluvoxamine / Q000008:administration & dosage*; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D018687:Antidepressive Agents, Second-Generation; D014150:Antipsychotic Agents; D019388:Cytochrome P-450 CYP1A2; D003024:Clozapine; D016666:Fluvoxamine