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

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.