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.