Cytochrome mirtazapine metabolism

Describe the metabolites of mirtazapine and the cytochrome P450 isozymes involved. The three active metabolites formed from mirtazapine metabolism are 8-hydroxymirtazap-... 

Stormer E, von Moltke LL, Greenblatt DJ. Scaling drug biotransformation data from cDNA-expressed cytochrome P-450 to human liver a comparison of relative activity factors and human liver abundance in studies of mirtazapine metabolism. J Pharmacol Exp Ther 2000a 295 793-801. 

Mirtazapine is rapidly absorbed from the gastrointestinal tract and achieves peak plasma concentrations within 2 hours of oral administration. It exhibits linear pharmacokinetics and is metabolized through the CYP450-2D6, CYP450-3A4, and, possibly, CYP450-1A2 systems (Owen and Nemeroff, 1998). Mirtazapine does not induce or inhibit any of the cytochrome systems. Only one of mirtazapine s metabolites, des-... 

Mirtazapine does not significantly inhibit hepatic cytochrome P450 enzymes. Additive effects may occur when mirtazapine is combined with other drugs with sedative or vascular effects. Mirtazapine should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI. When it is combined with fluvoxamine, a potent inhibitor of P450 enzymes— including 1A2, 2D6, and 3A4, which metabolizes mirtazapine—the plasma concentration of mirtazapine may be increased by up to fourfold (AnttUa et al. 2001 Demers et al. 2001). 

Verhoeven CHJ, Vos RME, Bogaards JJP. Characterization and inhibition of human cytochrome P450 enzymes involved in the in vitro metabolism of mirtazapine. Presentation at International Symposium on Microsomes and Drug Oxidations, Los Angeles, July 21-24, 1996. 

Mirtazapine is rapidly absorbed from the gut, is highly protein-bound, and extensively metabolized by cytochrome P450. The metabolites, which are active, are excreted in the urine, following glucuronidation. 

Stormer E, von Moltke LL, Shader Rl, et al. Metabolism of the antidepressant mirtazapine in vitro contribution of cytochromes P-450 1A2, 2D6, and 3A4. Drug Metab Dispos 2000 28 1168-1175. 

The cytochrome P450 isoenzyme CYP2D6 is inhibited by fluoxetine and paroxetine and CYP1A2 is inhibited by fluvoxamine. Both of these isoenzymes are involved in the metabolism of mirtazapine, which may explain the raised mirtazapine levels reported. 

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