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

Abstract

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×(number of CYP2D6*10 alleles) (R=0.279, p=0.023, coefficient of determination (R²)=0.078).

Conclusion: Homozygous CYP2D6*10 alleles and smoking have a significant impact on the metabolism of S-(+)-MIR in Japanese patients.

Key words

mirtazapine - enantiomer - CYP2D6*10 - pharmacokinetics - pharmacogenetics

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