8-Hydroxylation and Glucuronidation of Mirtazapine in Japanese Psychiatric Patients: Significance of the Glucuronidation Pathway of 8-Hydroxy-Mirtazapine

Introduction  To investigate the metabolism of mirtazapine( MIR) in Japanese psychiatric patients, we determined the plasma levels of MIR, N -desmethylmirtazapine (DMIR), 8-hydroxy- mirtazapine(8-OH- MIR), mirtazapine glucuronide( MIR-G), and 8-hydroxy- mirtazapine glucuronide(8-OH- MIR-G). Methods  Seventy-nine Japanese psychiatric patients were treated with MIRfor 1–8 weeks to achieve a steady-state concentration. Plasma levels of MIR, DMIR, and 8-OH- MIRwere determined using high-performance liquid chromatography. Plasma concentrations of MIR-G and 8-OH- MIR-G were determined by total MIRand total 8-OH- MIR(i. e., concentrations after hydrolysis) minus unconjugated MIRand unconjugated 8-OH- MIR, respectively. Polymerase chain reaction was used to determine CYP2D6genotypes. Results  Plasma levels of 8-OH- MIRwere lower than those of MIRand DMIR (median 1.42 nmol/L vs. 92.71 nmol/L and 44.96 nmol/L, respectively). The plasma levels (median) of MIR-G and 8-OH- MIR-G were 75.00 nmol/L and 111.60 nmol/L, giving MIR-G/ MIRand 8-OH- MIR-G/8-OH- MIRratios of 0.92 and 59.50, respectively. Multiple regression analysis revealed that smoking was correlated with the plasma MIRconcentration (dose- and body weight–corrected, p=0.040) and that age (years) was significantly correlated with the plasma DMIR concentration (dose- and body weight–corrected, p=0.018). The steady-state plasma concentrations of MIRand its metabolites were unaffected by the number of CYP2D6*5 and CYP2D6*10 alleles. Discussion  The plasma concentration of 8-OH- MIRwas as low as 1.42 nmol/L, whereas 8-OH- MIR-G had an approximate 59.50 times higher concentration than 8-OH- MIR, suggesting a significant role for hydroxylation of MIRand its glucuronidationin the Japanese population.