Effects of genetic polymorphism of CYP1A2 inducibility on the steady-stateplasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine in depressed Japanese patients

The effects of a genetic polymorphism of inducibility of cytochrome P450 (C YP) 1A2 on the steady-state plasma concentrations of trazodone and its acti ve metabolite, m-chlorophenylpiperazine, were studied in order to clarify i f these steady-state plasma concentrations are dependent on the CYP1A2 poly morphism. 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 li quid chromatographic method, and were corrected to the mean body weight for analyses. A point mutation from guanine (wild type) to adenine (mutated ty pe) at position -2964 in the 5 ' -flanking region of CYP1A2 gene was identi fied by polymerase chain reaction fragment length polymorphism method. The mean steady-state plasma concentration of trazodone, but not m-chlorophenyl piperazine was significantly (P <0.05) lower in smokers than in non-smokers . Twenty-two smokers had 16 homozygotes of the wild type allele, 5 heterozy gotes of the wild type and mutated alleles, and one homozygote of the mutat ed allele. There was no significant difference in the mean steady-state pla sma concentration of trazodone or m-chlorophenylpiperazine between smokers with no mutation and those with mutation, although one homozygote of the mu tated allele had the highest steady-slate 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 concentrat ion of trazodone or m-chlorophenylpiperazine in most of the smokers treated with trazodone.