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Vol. 28, Issue 10, 1168-1175, October 2000

Metabolism of the Antidepressant Mirtazapine In Vitro: Contribution of Cytochromes P-450 1A2, 2D6, and 3A4

Elke Störmer, Lisa L. von Moltke, Richard I. Shader, and David J. Greenblatt

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts

The metabolism of the antidepressant mirtazapine (MIR) was investigated in vitro using human liver microsomes (HLM) and recombinant enzymes. Mean Km values (±S.D., n = 4) were 136 (±44) µM for MIR-hydroxylation, 242 (±34) µM for N-demethylation, and 570 (±281) µM for N-oxidation in HLM. Based on the Km and Vmax values, MIR-8-hydroxylation, N-demethylation, and N-oxidation contributed 55, 35, and 10%, respectively, to MIR biotransformation in HLM at an anticipated in vivo liver MIR concentration of 2 µM. Recombinant CYP predicted a 65% contribution of CYP2D6 to MIR-hydroxylation at 2 µM MIR, decreasing to 20% at 250 µM. CYP1A2 contribution increased correspondingly from 30 to 50%. In HLM, quinidine and alpha -naphthoflavone reduced MIR-hydroxylation to 75 and 45% of control, respectively, at 250 µM MIR. A >50% contribution of CYP3A4 to MIR-N-demethylation at <1 µM MIR was indicated by recombinant enzymes. In HLM, ketoconazole (1 µM) reduced N-desmethylmirtazapine formation rates to 60% of control at 250 µM. Twenty percent of MIR-N-oxidation was accounted for by CYP3A4 at 2 µM MIR, increasing to 85% at 250 µM, while CYP1A2 contribution decreased from 80 to 15%. Ketoconazole reduced MIR-N-oxidation to 50% of control at 250 µM. MIR did not substantially inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP1E2, and CYP3A4 activity in vitro. Induction/inhibition or genetic polymorphisms of CYP2D6, CYP1A2, and CYP3A4 may affect MIR metabolism, but involvement of several enzymes in different metabolic pathways may prevent large alterations in in vivo drug clearance.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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