title: VKORC1-dependent pharmacokinetics of intravenous and oral phylloquinone (vitamin K1) mixed micelles formulation.
abstract: OBJECTIVE
  The pharmacokinetics of phylloquinone (vitamin K1) were evaluated in healthy human adult volunteers (15 male and 15 female) following oral and intravenous administration of a mixed micelles formulation (Konakion MM 2 mg) in an open label study design. The subjects were allocated to one of three genotype-specific groups (n = 10 in each group) in terms of VKORC1 promoter polymorphism c.-1639 G > A to explore the relationship between genotype and pharmacokinetic parameters.
  
  
  METHODS
  Blood samples were collected for up to 24 h after administration. Phylloquinone serum levels were determined by reversed phase HPLC with fluorometric detection after post-column zinc reduction. Pharmacokinetic evaluation was performed using non-compartmental analysis.
  
  
  RESULTS
  Pharmacokinetic analysis of serum phylloquinone concentration versus time profiles revealed significant differences in the main pharmacokinetic parameters between groups. Upon oral administration, VKORC1 AG carriers showed 41 % higher mean bioavailability (p = 0.01) compared with homozygous AA individuals. Furthermore, AG subjects exhibited 30 % (p = 0.042) and 36 % (p = 0.021) higher mean AUC compared with GG and AA respectively. Terminal half-life was 32 % and 27 % longer for AG carriers in comparison to GG (p = 0.004) and AA (p = 0.015) genotypes respectively.
  
  
  CONCLUSIONS
  Pharmacokinetic differences indicated significant inter-individual variance of vitamin K fate in the human body. The influence of the VKORC1 promoter polymorphism c.-1639 G > A on the pharmacokinetic properties of phylloquinone could be demonstrated in humans. To gain deeper insight in other potential genetic determinants of systemic vitamin K exposure, further correlation of the phenotype-genotype relationship of different players in vitamin K turnover has to be gained.
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Clinics Bonn, Sigmund- Freud-Strasse 25, 53127 Bonn, Germany. marinova.milka@gmail.com
authors.forename: Milka
authors.initials: M
authors.lastname: Marinova
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Olof
authors.initials: O
authors.lastname: Breuer
authors.forename: Heike
authors.initials: H
authors.lastname: Kölsch
authors.forename: Philipp
authors.initials: P
authors.lastname: Westhofen
authors.forename: Matthias
authors.initials: M
authors.lastname: Watzka
authors.forename: Martin
authors.initials: M
authors.lastname: Mengel
authors.forename: Birgit
authors.initials: B
authors.lastname: Stoffel-Wagner
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Coch
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D005260:Female; D005470:Fluorometry; D005858:Germany; D006207:Half-Life; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007275:Injections, Intravenous; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008823:Micelles; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D010837:Vitamin K 1 / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D064417:Vitamin K Epoxide Reductases; D014815:Vitamins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D008823:Micelles; D014815:Vitamins; D010837:Vitamin K 1; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases