Neue Einsichten in die orale Antikoagulationstherapie mit Cumarinen

Zusammenfassung

Die Identifizierung der Vitamin-K-Epoxid-Reduktase (VKORC1) hat maßgeblich zu einem besseren Verständnis des Vitamin-K-Zyklus beigetragen. Das VKORC1-Protein konnte als das molekulare Target der Cumarine charakterisiert werden und stellt das geschwindigkeitsbestimmende Enzym des Vitamin-K-Zyklus und möglicherweise die alleinige Komponente der VKOR-Aktivität dar. Mutationen und Polymorphismen innerhalb der translatierten und nicht translatierten Regionen des VKORC1-Gens verursachen partielle bis totale Cumarin-Resistenz und -Sensitivität. Die Verfügbarkeit einer molekulargenetischen Diagnostik (VKORC1, CYP2C9) und einer Laboranalytik mittels HPLC (zur Bestimmung des Cumarin-, Vitamin-K- und Vitamin- K-Epoxidspiegels) ist hilfreich in der Detektion hereditärer und erworbener Einflussgrößen der Cumarintherapie und könnte zukünftig für eine individualisierte, risikoärmere orale Antikoagulationstherapie zum Einsatz kommen.

Eine niedrig dosierte tägliche Vitamin-K-Supplementierung scheint geeignet, die Sicherheit einer oralen Antikoagulationstherapie mit Cumarinen zu verbessern. Bei der Entwicklung neuer und auf molekularer Ebene selektiv wirkender oraler Antikoagulanzien wird sich somit die Frage nach gleich guter Effektivität und Sicherheit im Vergleich zu den ˶alten“ Antikoagulanzien stellen. Gerade auch unter dem Aspekt der Ökonomie könnten die bewährten Cumarine durch eine pharmakogenetisch und nutritiv adaptierte Therapieoptimierung eine Renaissance erfahren.

Summary

The recent identification of vitamin K epoxid-reductase complex (VKORC1) contributed significantly to our mechanistic understanding of the vitamin K cycle. VKORC1 protein is targeted by Coumarins. Its enzymatic activity represents the rate-limiting step in the vitamin K cycle and γ-carboxylation of vitamin K dependent proteins. Possibly, VKORC1 is the only component of VKOR activity. Mutations as well as polymorphisms in coding and non-coding regions of the VKORC1 gene have been shown to cause both partial to total coumarin resistance and coumarin sensitivity. Availability of molecular diagnostics (VKORC1, CYP2C9) and laboratory analysis by HPLC (determination of coumarin, vitamin K and vitamin K epoxide levels) is helpful in detection of hereditary and acquired factors influencing coumarin therapy.

In the future, these tools might lead to an individualized and safer oral anticoagulation therapy. Furthermore, daily low-dose vitamin K supplementation may improve stability of coumarin-based anticoagulation. In the perspective of the coming new oral anticoagulants, the efficacy and safety profile of the ˶old“ anticoagulants is of major importance. The well established and oeconomic coumarin drugs will benefit from a pharmacogenetic and nutritive adjusted optimization of therapy.

Schlüsselwörter

VKORC1 - Vitamin-K-Zyklus - Cumarin

Keywords

VKORC1 - vitamin K cycle - coumarin

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