In Vitro and In Vivo Studies on the Disposition of Mirtazapine in Humans

Abstract

The novel antidepressant mirtazapine is a racemate with both noradrenergic and serotonergic potentiating effects. In vitro metabolism of racemic mirtazapine was studied in (a) microsomes from cells expressing different cytochrome P450 (CYP) enzymes and (b) human liver microsomes from 10 subjects and compared with the rate of metabolism of 4 substrates of specific CYP enzymes: ethoxyresorufin (CYP1A2), diclofenac (CYP2C9), bufuralol (CYP2D6) and testosterone (CYP3A4). These experiments suggested that the 8-hydroxylation of mirtazapine is catalysed by CYP2D6, and that the N(2)-demethylation and N(2)-oxidation are catalysed by CYP3A4. Mirtazapine was shown to be a competitive inhibitor of the CYP2D6 mediated hydroxylation of bufuralol in vitro, but with a 10 times higher inhibition constant (Ki) than for fluoxetine, i.e. mirtazapine is a much weaker inhibitor. To investigate the importance of CYP2D6 for the in vivo disposition of mirtazapine, a single oral dose of racemic mirtazapine was given to 7 extensive (EM) and 7 poor metabolisers (PM) of debrisoquine. Plasma concentrations (sum of enantiomers) of mirtazapine and its demethyl metabolite were monitored over 3 days. Oral plasma clearance of mirtazapine was very similar in EM and PM of debrisoquine (0.51 ±0.18 and 0.49 ± 0.22 L/h/kg, respectively; NS). In addition, the mean half-lives were almost identical: 23.4 and 23.3 hours, respectively. Plasma concentrations of demethylmirtazapine were also very similar in EM and PM. This in vivo study indicates that the major enantiomer of mirtazapine in plasma is not metabolised by CYP2D6, but it cannot be excluded that the minor one is. A study using a chiral analysis of the 2 enantiomers is currently ongoing. From a clinical point of view it is unlikely that mirtazapine would inhibit the metabolism of coadministered drugs metabolised by CYP1A2, CYP2D6 or CYP3A4. The panel study on EM and PM shows that strong inhibitors of CYP2D6 would not be expected to affect the concentration of the major mirtazapine enantiomer, but the effect on the minor enantiomer cannot be predicted.