Metabolism of the antidepressant mirtazapine in vitro: Contribution of cytochromes P-450 1A2, 2D6, and 3A4

The metabolism of the antidepressant mirtazapine (MIR) was investigated in vitro using human liver microsomes (HLM) and recombinant enzymes. Mean K-m values (+/-S.D., n = 4) were 136 (+/-44) mu M for MIR-hydroxylation, 242 (/-34) mu M for N-demethylation, and 570 (+/-281) mu M for N-oxidation in HL M. Based on the K-m and V(m)ax values, MIR-8-hydroxylation, N-demethylation , and N-oxidation contributed 55, 35, and 10%, respectively, to MIR biotran sformation in HLM at an anticipated in vivo liver MIR concentration of 2 mu M. Recombinant CYP predicted a 65% contribution of CYP2D6 to MIR-hydroxyla tion at 2 mu M MIR, decreasing to 20% at 250 mu M. CYP1A2 contribution incr eased correspondingly from 30 to 50%. In HLM, quinidine and alpha-naphthofl avone reduced MIR-hydroxylation to 75 and 45% of control, respectively, at 250 mu M MIR. A >50% contribution of CYP3A4 to MIR-N-demethylation at <1 mu M MIR was indicated by recombinant enzymes. In HLM, ketoconazole (1 mu M) reduced N-desmethylmirtazapine formation rates to 60% of control at 250 mu M. Twenty percent of MIR-N-oxidation was accounted for by CYP3A4 at 2 mu M MIR, increasing to 85% at 250 mu M, while CYP1A2 contribution decreased fro m 80 to 15%. Ketoconazole reduced MIR-N-oxidation to 50% of control at 250 mu M. MIR did not substantially inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CY P1E2, and CYP3A4 activity in vitro. Induction/inhibition or genetic polymor phisms of CYP2D6, CYP1A2, and CYP3A4 may affect MIR metabolism, but involve ment of several enzymes in different metabolic pathways may prevent large a lterations in in vivo drug clearance.