Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol.

Article Details

Citation

Ufer M

Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol.

Clin Pharmacokinet. 2005;44(12):1227-46.

PubMed ID
16372822 [ View in PubMed
]
Abstract

Vitamin K antagonists belong to the group of most frequently used drugs worldwide. They are used for long-term anticoagulation therapy, and exhibit their anticoagulant effect by inhibition of vitamin K epoxide reductase. Each drug exists in two different enantiomeric forms and is administered orally as a racemate. The use of vitamin K antagonists is complicated by a narrow therapeutic index and an unpredictable dose-response relationship, giving rise to frequent bleeding complications or insufficient anticoagulation. These large dose response variations are markedly influenced by pharmacokinetic aspects that are determined by genetic, environmental and possibly other yet unknown factors. Previous knowledge in this regard principally referred to warfarin. Cytochrome P450 (CYP) 2C9 has clearly been established as the predominant catalyst responsible for the metabolism of its more potent S-enantiomer. More recently, CYP2C9 has also been reported to catalyse the hydroxylation of phenprocoumon and acenocoumarol. However, the relative importance of CYP2C9 for the clearance of each anticoagulant substantially differs. Overall, the CYP2C9 isoenzyme appears to be most important for the clearance of warfarin, followed by acenocoumarol and, lastly, phenprocoumon. The less important role of CYP2C9 for the clearance of phenprocoumon is due to the involvement of CYP3A4 as an additional catalyst of phenprocoumon hydroxylation and significant excretion of unchanged drug in bile and urine, while the elimination of warfarin and acenocoumarol is almost completely by metabolism. Consequently, the effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are also least pronounced in the case of phenprocoumon; this drug seems preferable for therapeutic anticoagulation in poor metabolisers of CYP2C9. In addition to these vitamin K antagonists, oral thrombin inhibitors are currently under clinical development for the prevention and treatment of thromboembolism. Of these, ximelagatran has recently gained marketing authorisation in Europe. These novel drugs all feature some major advantages over traditional anticoagulants, including a wide therapeutic interval, the lack of anticoagulant effect monitoring and a low drug-drug interaction potential. However, they are also characterised by some pitfalls. Amendments of traditional anticoagulant therapy, including self-monitoring of international normalised ratio values or prospective genotyping for individual dose-tailoring may contribute to the continuous use of warfarin, phenprocoumon and acenocoumarol in the future.

DrugBank Data that Cites this Article

Drugs
Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
AcenocoumarolCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
WarfarinCytochrome P450 1A2ProteinHumans
Unknown
Substrate
Details
WarfarinCytochrome P450 2C18ProteinHumans
Unknown
Substrate
Details
WarfarinCytochrome P450 2C19ProteinHumans
Unknown
Substrate
Inhibitor
Details
WarfarinCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
WarfarinCytochrome P450 2C9ProteinHumans
Unknown
Substrate
Inducer
Details
WarfarinCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
XimelagatranCytochrome P450 2C9ProteinHumans
Unknown
Substrate
Details
Drug Reactions
Reaction
Details
Details
Details
Details
Details
Details
Details
Details
Details