In vitro and in vivo studies on the disposition of mirtazapine in humans

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