PHARMACOKINETICS AND BIOTRANSFORMATION OF MIRTAZAPINE IN HUMAN VOLUNTEERS

This paper investigated the pharmacokinetics and biotransformation of mirtazapine in healthy human volunteers. The results showed that the a rea under the plasma drug concentration-time curve (AUG) of mirtazapin e in human plasma appeared to be three times higher than the AUC of de methylmirtazapine. As mirtazapine is marketed as a racemic mixture and both enantiomers possess pharmacological properties essential for the overall activity of the racemate, the pharmacokinetics of mirtazapine were examined and appeared to be enantioselective. The R(-)-enantiome r showed the longest elimination half-life from plasma. This was ascri bed to the preferred formation of a quaternary ammonium glucuronide of the R(-)-enantiomer. This glucuronide may be deconjugated, leading to a further circulation of the parent compound, thus causing a prolonga tion in the elimination half-life. The S(+)-enantiomer was preferentia lly metabolised into an 8-hydroxy glucuronide. Other metabolic transfo rmation pathways found for mirtazapine were demethylation and N-oxidat ion. Mirtazapine was extensively metabolised and almost completely exc reted in the urine (over 80%) and faeces within a few days after oral administration.