Pharmacokinetics of mirtazapine: enantioselective effects of the CYP2D6 ultra rapid metabolizer genotype and correlation with adverse effects.
Enantiomerically pure drugs and genotyping are promising approaches to achieve optimization in antidepressant therapy. Mirtazapine is a mixed noradrenergic serotoninergic antidepressant used as a racemate. We analyzed pharmacokinetics of its enantiomers in relation to CYP2D6 genotype and in relation to its adverse effects. Mirtazapine was enantioselectively absorbed from the gut with a rate constant of 0.2 min-1 for S+, but 0.08 min-1 for R- mirtazapine. Kinetics of R- mirtazapine was only marginally dependent on CYP2D6 genotype, but total clearance of the S+ enantiomer were 1.3, 2.3, and 3.4 L min-1 in poor, extensive, and ultrarapid metabolizers of CYP2D6 substrates with apparent substantial first-pass metabolism in rapid and ultrarapid metabolizers. Mirtazapine effects on heart rate and blood pressure correlated much more strongly with R- then with S+ concentrations, whereas sedation correlated similarly with both enantiomers. At least concerning some adverse effects, it might be worthwhile to study further mirtazapine enantiospecifically.
Brockmöller
J
J
Department of Clinical Pharmacology, Georg August University of Göttingen, Göttingen, Germany.
Meineke
I
I
Kirchheiner
J
J
D000483:Alleles; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D001794:Blood Pressure / Q000187:drug effects; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D020440:Gene Duplication; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008803:Mianserin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000078785:Mirtazapine; D013237:Stereoisomerism
D018687:Antidepressive Agents, Second-Generation; D008803:Mianserin; D000078785:Mirtazapine; D019389:Cytochrome P-450 CYP2D6