1. ¹Department of Clinical Pharmacology, Georg August University of Göttingen, Göttingen, Germany
2. ²Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany

Correspondence: Julia Kirchheiner, (julia.kirchheiner@uni-ulm.de)

Received 4 November 2006; Accepted 9 January 2007; Published online 28 February 2007.

Abstract

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.