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.
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.
Ozdemir
V
V
Department of Pharmacology, University of Toronto, Ontario, Canada.
Kalow
W
W
Okey
A B
AB
Lam
M S
MS
Albers
L J
LJ
Reist
C
C
Fourie
J
J
Posner
P
P
Collins
E J
EJ
Roy
R
R
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
D018687:Antidepressive Agents, Second-Generation; D014150:Antipsychotic Agents; D019388:Cytochrome P-450 CYP1A2; D003024:Clozapine; D016666:Fluvoxamine