Impact of the CYP2D6 ultrarapid metabolizer genotype on mirtazapine pharmacokinetics and adverse events in healthy volunteers.
BACKGROUND
In vitro studies showed that biotransformation of the antidepressant drug mirtazapine is mediated by cytochrome P-450 enzymes CYP1A2, CYP2D6, and CYP3A4 with CYP2D6 contributing about 35% to total mirtazapine biotransformation. We hypothesized that ultrarapid metabolizers (defined as carriers of the CYP2D6 gene duplication plus another functional allele) have a risk for therapeutic failure due to too low tissue concentrations.


METHODS
Ten healthy male volunteers carrying 1 CYP2D6 duplication allele and 1 wild-type allele, 12 carriers of 2 CYP2D6 wild-type alleles and 3 carriers of 2 functionally inactive alleles received a single dose of 45 mg racemic mirtazapine and plasma concentrations were measured from 0 to 58 hours.


RESULTS
Median total clearance of racemic mirtazapine (Cl/F) was 20.1, 39.7, and 49.8 L/h in carriers of 0, 2, and 3 active genes of CYP2D6 (P = 0.002, trend test) and the median maximum plasma concentrations were 129, 159, and 76 mug/L in these 3 groups. The effects on maximal blood concentrations may indicate a contribution of CYP2D6 on mirtazapine first-pass metabolism. A trend with lower concentrations in the high-activity CYP2D6 genotypes was also seen for the active metabolite desmethylmirtazapine, but without any significance. Mirtazapine concentrations showed a significant correlation with diastolic and systolic blood pressure (P = 0.05) and the correlation was even stronger when taking total mirtazapine (mirtazapine plus desmethylmirtazapine, P = 0.03), but neither blood pressure nor heart rate effects were correlated with CYP2D6 genotype.


CONCLUSIONS
Consistent with the in vitro data, the genetically polymorphic enzyme CYP2D6 contributed to about 25% of total clearance in carriers of only one active allele and up to 55% in the genetically defined ultrarapid metabolizers. But the effect of the CYP2D6 gene duplication was lower than expected and high CYP2D6 activity may only explain a very small fraction of the cases with therapeutic failure in treatment with mirtazapine.
Kirchheiner
Julia
J
Institute of Clinical Pharmacology, Humboldt University Berlin, Germany. Julia.kirchheiner@charite.de
Henckel
Hanns-Benjamin
HB
Meineke
Ingolf
I
Roots
Ivar
I
Brockmöller
Jürgen
J
D000328:Adult; D019540:Area Under Curve; D016001:Confidence Intervals; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D005787:Gene Frequency / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008803:Mianserin / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D000078785:Mirtazapine
D008803:Mianserin; D000078785:Mirtazapine; D019389:Cytochrome P-450 CYP2D6