Warfarin metabolism in man: identification of metabolites in urine
01 May 1970-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 49, Iss: 5, pp 907-913
TL;DR: These are the first studies to document the metabolic fate of warfarin in the normal human and two diastereoisomer alcohols were identified, structurally similar to pharmacologically active coumarin derivatives.
Abstract: After administration of the coumarin anticoagulant racemic warfarin to normal humans, seven fluorescent compounds were chromatographically separated from extracts of their urine. Four of these were identified using mass spectrometry, thin-layer chromatography, and ultraviolet absorption spectroscopy. One metabolic pathway, reduction of the acetonyl side chain of warfarin, resulted in the formation of a second asymmetric carbon atom, and two diastereoisomer alcohols were identified. These warfarin alcohols are structurally similar to pharmacologically active coumarin derivatives. They have not been reported in animal studies. In addition, 6- and 7-hydroxywarfarin were identified. These are the first studies to document the metabolic fate of warfarin in the normal human.
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TL;DR: Interactions of Individual Drugs with Coumarins A very large number of drugs have been suspected of interacting with coumarin anticoagulants, and some such anecdotal reports, even when invalidated by subsequent careful studies, have gradually developed into "facts" and are endlessly repeated in the literature.
Abstract: Interactions of Individual Drugs with Coumarins A very large number of drugs have been suspected of interacting with coumarin anticoagulants. Often, this suspicion has stemmed from the interpretation of a single clinical event, and one of the many other factors that influence the relation between coumarin dose and hypoprothrombinemic response may actually have been responsible. Reports of such clinical impressions are useful, but they should be considered mere leads and should be followed up by controlled investigations. Unfortunately, some such anecdotal reports, even when invalidated by subsequent careful studies, have gradually developed into "facts" and are endlessly repeated in the . . .
286 citations
TL;DR: Overall, the CYP2C9 isoenzyme appears to be most important for the clearance of warfarin, followed by acenocoumarol and, lastly, phenprocoumon; this drug seems preferable for therapeutic anticoagulation in poor metabolisers of CYP1C9.
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.
283 citations
TL;DR: It is concluded that inhibition of the metabolism of S warfarin provides one mechanism for the augmented anticoagulation which follows phenylbutazone.
Abstract: An examination of the metabolic fate of the R and the S isomers of warfarin revealed that the two isomers were metabolized by different routes. R warfarin was oxidized to 6-hydroxywarfarin and was reduced to the (R,S) warfarin alcohol. In contrast, S warfarin was oxidized to 7-hydroxywarfarin and was reduced to the (S,S) warfarin alcohol. S warfarin was also oxidized to 6-hydroxywarfarin. These observations suggested that interactions between warfarin and other drugs might be manifest stereo-specifically, i.e., have a different effect on the isomers of warfarin, so a series of experiments were conducted with each isomer of warfarin, before and after phenylbutazone. The plasma clearance of S warfarin was slowed from 3.1 to 1.1% per h in one subject and from 2.3 to 1.6% per h in another. In contrast, the clearance of R warfarin was increased from 1.5 to 3.0% per h and from 0.9 to 1.6% per h in two subjects after phenylbutazone. The rate of clearance of racemic warfarin was unaffected by phenylbutazone; the depression of the rate of clearance of the S isomer masked the stimulation of the clearance of the R isomer. Since S warfarin is five times more potent an anticoagulant than R warfarin, it is concluded that inhibition of the metabolism of S warfarin provides one mechanism for the augmented anticoagulation which follows phenylbutazone.
272 citations
124 citations
TL;DR: There are several well established pharmacokinetic drug interactions with warfarin and there is a wide awareness of the drugs most likely to reduce anticoagulant effects by enzyme induction and alternative drugs can be used.
Abstract: Warfarin is clinically the most widely used oral anticoagulant and its properties have been extensively studied. Assay method for these compounds have until recently been relatively nonspecific. The advent of chromatographically based techniques has enabled re-evaluation of the pharmacokinetics of oral anticoagulants, but most work continues to involve warfarin. The most important recent work has concerned the different anticoagulant potencies and metabolic pathways of the optical isomers of some of these drugs. The effects of age and some diseases on pharmacokinetics of warfarin have been examined but much remains to be done, especially with oral anticoagulants other than warfarin. There are several well established pharmacokinetic drug interactions with warfarin. There is a wide awareness of the drugs most likely to reduce anticoagulant effects by enzyme induction and alternative drugs can be used. Mechanisms of some interactions have been re-investigated. In vivo drug displacement interactions are complicated by the correlation between hepatic clearance of these drugs and the size of the unbound fraction in plasma. The interactions between phenylbutazone and warfarin and metronidazole and warfarin, resulting in potentiation of anticoagulant effect have been suggested to be due mainly to an inhibition of the metabolism of the more potent S isomer of warfarin.
119 citations
References
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TL;DR: Risks of toxicity on the one hand and of failure to anticoagulate adequately on the other can be reduced by determining dicumarol half-life before starting long-term therapy, as well as in unrelated volunteers administered progressively larger doses at 10-day intervals.
Abstract: The mean half-life of dicumarol in the plasma of seven sets of identical and seven sets of fraternal twins after a single oral dose of 4 mg/kg was 43.6±SD 17.9 hr. Half-lives ranged from 7 to 74 hr in these 28 normal adults not receiving other drugs for 2 wk preceding dicumarol administration. Large differences among unrelated individuals in dicumarol half-life disappeared almost completely in identical twins, but persisted to some extent in most sets of fraternal twins. These results indicate that marked differences among subjects in dicumarol half-life are under genetic rather than environmental control. Reproducibility of values for dicumarol half-life was demonstrated. A direct relationship between the dose and the half-life of dicumarol occurred in unrelated volunteers administered progressively larger doses at 10-day intervals. Dose dependence of the half-life of a drug results in increased variability of half-life and hence in greater risks of toxicity on long-term therapy. Risks of toxicity on the one hand and of failure to anticoagulate adequately on the other can be reduced by determining dicumarol half-life before starting long-term therapy. Half-lives for dicumarol and phenylbutzone tended to be correlated in the 28 twins, but no correlation occurred between dicumarol and antipyrine half-lives.
156 citations
153 citations
TL;DR: The work described here was undertaken to determine the similarity in this respect between man and rat or rabbit and the metabolism of coumarin was determined.
Abstract: COUMARIN is a naturally occurring constituent of many plants, and has been used extensively as a flavouring material, although its use for this purpose is now banned in many countries. Its toxic effects on many species of animal have been reported1–6 and its metabolism in rats and rabbits has been investigated7–9. No study has been made of the metabolism of coumarin in man, and the work described here was undertaken to determine the similarity in this respect between man and rat or rabbit.
137 citations
TL;DR: The variability of response of human beings to many drugs is usually continuous and gives a unimodal frequency-distribution curve for the drug action measured.
Abstract: THE variability of response of human beings to many drugs is usually continuous and gives a unimodal frequency-distribution curve for the drug action measured. These unimodal distribution curves ar...
125 citations