title: Effects of genetic polymorphism of CYP1A2 inducibility on the steady-state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine in depressed Japanese patients.
abstract: The effects of a genetic polymorphism of inducibility of cytochrome P450 (CYP) 1A2 on the steady-state plasma concentrations of trazodone and its active metabolite, m-chlorophenylpiperazine, were studied in order to clarify if these steady-state plasma concentrations are dependent on the CYP1A2 polymorphism. Fifty-eight Japanese depressed patients received trazodone 150 mg/day at bedtime. The steady-state plasma concentrations of trazodone and m-chlorophenylpiperazine were measured in duplicate using high performance liquid chromatographic method, and were corrected to the mean body weight for analyses. A point mutation from guanine (wild type) to adenine (mutated type) at position -2964 in the 5'-flanking region of CYP1A2 gene was identified by polymerase chain reaction fragment length polymorphism method. The mean steady-state plasma concentration of trazodone, but not m-chlorophenylpiperazine was significantly (P<0.05) lower in smokers than in non-smokers. Twenty-two smokers had 16 homozygotes of the wild type allele, 5 heterozygotes of the wild type and mutated alleles, and one homozygote of the mutated allele. There was no significant difference in the mean steady-state plasma concentration of trazodone or m-chlorophenylpiperazine between smokers with no mutation and those with mutation, although one homozygote of the mutated allele had the highest steady-state plasma concentration of trazodone in smokers. The present study thus suggests that CYP1A2 polymorphism does not necessarily have predictive value of the steady-state plasma concentration of trazodone or m-chlorophenylpiperazine in most of the smokers treated with trazodone.
authors.affiliation: Department of Neuropsychiatry, Hirosaki University School of Medicine, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Mihara
authors.forename: T
authors.initials: T
authors.lastname: Kondo
authors.forename: A
authors.initials: A
authors.lastname: Suzuki
authors.forename: N
authors.initials: N
authors.lastname: Yasui-Furukori
authors.forename: S
authors.initials: S
authors.lastname: Ono
authors.forename: K
authors.initials: K
authors.lastname: Otani
authors.forename: S
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000328:Adult; D000483:Alleles; D018687:Antidepressive Agents, Second-Generation / Q000097:blood* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000235:genetics; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000097:blood* / Q000493:pharmacokinetics*; D017354:Point Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012907:Smoking / Q000097:blood / Q000235:genetics; D013997:Time Factors; D014196:Trazodone / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D010879:Piperazines; D019388:Cytochrome P-450 CYP1A2; C015068:1-(3-chlorophenyl)piperazine; D014196:Trazodone