title: Impact of the CYP2D6 ultrarapid metabolizer genotype on mirtazapine pharmacokinetics and adverse events in healthy volunteers.
abstract: 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.
authors.affiliation: Institute of Clinical Pharmacology, Humboldt University Berlin, Germany. Julia.kirchheiner@charite.de
authors.forename: Julia
authors.initials: J
authors.lastname: Kirchheiner
authors.forename: Hanns-Benjamin
authors.initials: HB
authors.lastname: Henckel
authors.forename: Ingolf
authors.initials: I
authors.lastname: Meineke
authors.forename: Ivar
authors.initials: I
authors.lastname: Roots
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brockmöller
mesh_terms: 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
chemical_list: D008803:Mianserin; D000078785:Mirtazapine; D019389:Cytochrome P-450 CYP2D6