Factors Affecting Steady-state Plasma Concentrations of Enantiomeric Mirtazapine and its Desmethylated Metabolites in Japanese Psychiatric Patients

Introduction: This study evaluated the effects of the CYP2D6 * 10 genotype on steady-state plasma concentrations of enantiomeric mirtazapine (MIR) and N-desmethylmirtazapine (DMIR) in Japanese patients. Methods: Subjects were 77 Japanese patients treated with racemic MIR. Steady-state plasma concentrations of MIR and DMIR enantiomers were measured using stereoselective liquid chromatography. Polymerase chain reaction was used to determine the CYP2D6 genotypes. Results: After correcting for dose and body weight, smokers (n = 15) had significantly lower S-(+)-MIR than nonsmokers (n = 55) (15.1 +/- 17.8 vs. 23.9 +/- 17.8 ng/mL/mg/kg, Kruskal-Wallis test, p = 0.034). One-way analysis of variance revealed that CYP2D6 * 10 homozygotes had significantly higher corrected plasma concentrations of S-(+)-MIR than the no-variant allele group (p = 0.034). Multiple regression analysis revealed a significant positive correlation between the number of CYP2D6 * 10 alleles and corrected plasma concentrations of S-(+)-MIR. These results yielded the following final model: corrected plasma concentration of S-(+)-MIR = 15.9 + 7.30 x (number of CYP2D6 * 10 alleles) (R = 0.279, p = 0.023, coefficient of determination (R-2) = 0.078). Conclusion: Homozygous CYP2D6 * 10 alleles and smoking have a significant impact on the metabolism of S-(+)-MIR in Japanese patients.