Pharmacokinetics of mirtazapine: Enantioselective effects of the CYP2D6 ultra rapid metabolizer genotype and correlation with adverse effects

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.