4-Hydroxycoumarin Oral Anticoagulants : Pharmacokinetics-Response Relationship

Thijssen, H. H. W.; Hamulyák, Karly; Willigers, Henriëtte M.

doi:10.1055/s-0038-1647630

Cited by 33 publications

(28 citation statements)

References 11 publications

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“…This is probably due to the higher V, values of the R-enantiomers (Tables 3 and 4). However, during therapy, blood levels range from 1 to 10 liM for warfarin (Holford, 1986) and from 60 to 600 nM for acenocoumarol (Thijssen et al, 1988). The concentration of the unbound drugs will be even lower.…”

Section: Resultsmentioning

confidence: 99%

Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Hermans

Thijssen

1993

British J Pharmacology

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1 To explain the large differences in (the stereoselectivity of) the clearances of the enantiomers of warfarin and acenocoumarol (4'-nitrowarfarin) their human liver microsomal metabolism has been studied and enzyme kinetic parameters determined. The effects of cimetidine, propafenone, sulphaphenazole, and omeprazole on their metabolism has been investigated. 2 The 4-hydroxycoumarins follow similar metabolic routes and are mainly hydroxylated at the 6-and 7-position (accounting for 63 to 99% of the metabolic clearances).3 Due to the lower Km values of R-and S-acenocoumarol and higher Vma. values of S-acenocoumarol, the overall metabolic clearances of R/S acenocoumarol exceed those of R/S warfarin 6 and 66 times respectively. 4 The metabolism of both compounds is stereoselective for the S-enantiomers, which is 10 times more pronounced in the case of acenocoumarol.5 Except for the 7-hydroxylation of the R-enantiomers (r = 0.90; P <0.025), the 6-and 7-hydroxylation rates of R/S warfarin do not correlate with those of R/S acenocoumarol. 6 Sulphaphenazole competitively inhibits the 7-and in some samples partly (up to 50%) the 6-hydroxylation of S-warfarin as well as the 7-hydroxylation of R-and S-acenocoumarol and the 6-hydroxylation of S-acenocoumarol (Kis ranging from 0.5-1.3 JAM).7 Omeprazole partly (40-80%) inhibits the 6-and 7-hydroxylation of R-warfarin (Ki = 99 and 117 pM) and of R-(Ki = 219 and 7.2 jAM) and S-acenocoumarol (Ki = 6.1 and 7.7 JiM) but not S-warfarin in a competitive manner. 8 Differences in the partial (up to 40%) inhibition of the metabolism of the enantiomers of the 4-hydroxycoumarins were also observed for the relatively weak inhibitors, propafenone and cimetidine. 9 The results suggest that the coumarin ring hydroxylations of both compounds are catalysed by different combinations of P450 isozymes. The 7-hydroxylation of R/S acenocoumarol and the 6-hydroxylation of S-acenocoumarol are at least partly conducted by (a) P450 isozyme(s) of the 2C subfamily different from P450 2C9 (the main S-warfarin 7-and 6-hydroxylase).

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Section: Resultsmentioning

confidence: 99%

Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Hermans

Thijssen

1993

British J Pharmacology

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“…The absence of a difference in factor II and factor VII in therapeutically anticoagulated patients on acenocoumarol may be explained by the fact that blood was collected 12-18 h after drug intake. With the use of acenocoumarol, due to its short half-life, factor VII fluctuates and the level is lowest about 16 h after drug intake [15]. Besides, the stratified analysis was based on relatively small numbers.…”

Section: Discussionmentioning

confidence: 99%

Levels of vitamin K-dependent procoagulant and anticoagulant proteins in over-anticoagulated patients

Beest

García

Meer

et al. 2002

Blood Coagulation& Fibrinolysis

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Coumarin anticoagulants impair the biological activity of the vitamin K-dependent procoagulant and anticoagulant proteins. There are no reports that focus on the levels of these proteins in over-anticoagulated patients. Therefore, we determined the levels of factor II, factor VII, factor IX and factor X, protein C and protein S in 25 randomly selected over-anticoagulated patients (International Normalized Ratio >/= 6.0) and in 25 matched, therapeutically anticoagulated patients with an International Normalized Ratio within the therapeutic zone. Furthermore, to study a possible effect of the cause of over-anticoagulation, coagulant levels were compared between 16 over-anticoagulated patients with fever in the preceding 2 weeks and 24 over-anticoagulated patients with stable congestive heart failure. The pattern of procoagulant level reductions in the three groups of over-anticoagulated patients was largely the same as in therapeutically anticoagulated patients: factor X was the lowest and factor IX the highest. The difference was that, in over-anticoagulated patients, factor VII was relatively low among the procoagulant factors compared with therapeutically anticoagulated patients. Protein C was lower than protein S in over-anticoagulated patients with congestive heart failure, but was similar to protein S in the other study groups. In over-anticoagulated patients with fever, the vitamin K-dependent coagulation proteins except factor X were significantly lower than in over-anticoagulated patients with congestive heart failure, especially factor VII and protein S.

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“…shown that this feature causes a fluctuation in the plasma levels of factor VII when acenoMechanical Prostheses. For patients with mechanical heart valves, long-term OAT is recoumarol is administered every 24 h [Thijsen et al, 1988]. commended, with an INR (international normalized ratio) between 3 and 4.5.…”

Section: Oas and Their Action Mechanismmentioning

confidence: 99%

A Guide to Oral Anticoagulant Therapy

Palareti¹

1998

Pathophysiol Haemos Thromb

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4-Hydroxycoumarin Oral Anticoagulants : Pharmacokinetics-Response Relationship

Cited by 33 publications

References 11 publications

Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Levels of vitamin K-dependent procoagulant and anticoagulant proteins in over-anticoagulated patients

A Guide to Oral Anticoagulant Therapy

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