Philipp Westhofen

Publications (3)12.66 Total impact

• Article: VKORC1-dependent pharmacokinetics of intravenous and oral phylloquinone (vitamin K1) mixed micelles formulation.

  Milka Marinova, Dieter Lütjohann, Olof Breuer, Heike Kölsch, Philipp Westhofen, Matthias Watzka, Martin Mengel, Birgit Stoffel-Wagner, Gunther Hartmann, Christoph Coch, Johannes Oldenburg
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  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. CONCLUSION: 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.
  European Journal of Clinical Pharmacology 08/2012; · 2.85 Impact Factor
• Article: Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1 (VKORC1L1) mediates vitamin K-dependent intracellular antioxidant function.

  Philipp Westhofen, Matthias Watzka, Milka Marinova, Moritz Hass, Gregor Kirfel, Jens Müller, Carville G Bevans, Clemens R Müller, Johannes Oldenburg
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  ABSTRACT: Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1 (VKORC1L1), expressed in HEK 293T cells and localized exclusively to membranes of the endoplasmic reticulum, was found to support both vitamin K 2,3-epoxide reductase (VKOR) and vitamin K reductase enzymatic activities. Michaelis-Menten kinetic parameters for dithiothreitol-driven VKOR activity were: K(m) (μM) = 4.15 (vitamin K(1) epoxide) and 11.24 (vitamin K(2) epoxide); V(max) (nmol·mg(-1)·hr(-1)) = 2.57 (vitamin K(1) epoxide) and 13.46 (vitamin K(2) epoxide). Oxidative stress induced by H(2)O(2) applied to cultured cells up-regulated VKORC1L1 expression and VKOR activity. Cell viability under conditions of no induced oxidative stress was increased by the presence of vitamins K(1) and K(2) but not ubinquinone-10 and was specifically dependent on VKORC1L1 expression. Intracellular reactive oxygen species levels in cells treated with 2,3-dimethoxy-1,4-naphthoquinone were mitigated in a VKORC1L1 expression-dependent manner. Intracellular oxidative damage to membrane intrinsic proteins was inversely dependent on VKORC1L1 expression and the presence of vitamin K(1). Taken together, our results suggest that VKORC1L1 is responsible for driving vitamin K-mediated intracellular antioxidation pathways critical to cell survival.
  Journal of Biological Chemistry 03/2011; 286(17):15085-94. · 4.77 Impact Factor
• Article: Polymorphisms in VKORC1 and GGCX are not major genetic determinants of vitamin K-dependent coagulation factor activity in Western Germans.

  Matthias Watzka, Philipp Westhofen, Moritz Hass, Milka Marinova, Bernd Pötzsch, Johannes Oldenburg
  Thrombosis and Haemostasis 09/2009; 102(2):418-20. · 5.04 Impact Factor