The clinical relevance of preclinical data: mirtazapine, a model compound.
This paper discusses how in vitro and preclinical in vivo studies might be of help for the interpretation and prediction of possible clinically relevant effects. The examples given refer to the data obtained with mirtazapine, a novel antidepressant with a dual mechanism of action, which can be best summarized as a noradrenergic and specific serotonergic antidepressant. Preclinical data on mirtazapine have shown that (i) its binding to plasma proteins is relatively low and non-specific; (ii) the contribution of its metabolites to the pharmacologic effect is negligible; (iii) it possesses high bioavailability, resulting in a low variance between individuals; (iv) it has no inducing or inhibiting effects on hepatic P450 enzymes; (v) it has a very low potential for clinically relevant pharmacokinetic interactions with other drugs; and (vi) its disposition is independent of polymorphic CYP2D6 activity. The available preclinical data on mirtazapine could be used to advise clinicians and to guide clinical practice.
Delbressine
L P
LP
Department of Drug Metabolism and Kinetics, N.V. Organon, Oss, The Netherlands. l.delbressine@organon.akzonobel.nl
Vos
R M
RM
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D001682:Biological Availability; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy*; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008657:Metabolic Clearance Rate; D008803:Mianserin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D000078785:Mirtazapine; D011110:Polymorphism, Genetic; D011485:Protein Binding
D000929:Antidepressive Agents, Tricyclic; D065607:Cytochrome P-450 Enzyme Inhibitors; D008803:Mianserin; D003577:Cytochrome P-450 Enzyme System; D000078785:Mirtazapine