Acenocoumarol metabolism

Intravenous methylprednisolone (1 g/day for 3 days) has been reported to inhibit the metabolism of oral anticoagulants (acenocoumarol and fluindione) in 10 patients, increasing the INR by 8 (range 5-20) (478). 

CICLOSPORIN ANTICOAGULANTS-ORAL 1. J ciclosporin levels when co-administered with warfarin or acenocoumarol 2.1 anticoagulant effect with warfarin and variable effect with acenocoumarol Competitive metabolism by CYP3A4 1. Watch for i efficacy of ciclosporin 2. Monitor INR at least weekly until stable... 

Cetirizine is a non-sedating metabolite of hydroxyzine (SEDA-18, 181) (SEDA-19, 172) (SEDA-21, 172) (SEDA-22, 178). There is only minor hepatic metabolism of cetirizine (1), which is excreted unchanged in the urine. It has not been associated with dysrhythmias. Skin reactions have been reported, and the anticoagulant activity of acenocoumarol may be potentiated (SEDA-22, 178). 

The authors proposed that ritonavir had induced CYP1A2, CYP1A4, and CYP2C9/19 activity, leading to increased metabolism, at least of acenocoumarol However, this effect was the opposite of what was expected, since ritonavir is a potent inhibitor of most hepatic isoenzymes. 

The effect of warfarin is potentiated by metronidazole (43,44). The mechanism is stereoselective inhibition by metronidazole of the metabolism of 5-warfarin, the more potent isomer (43). There is a similar interaction with acenocoumarol (45,46). 

The clinically used preparation of warfarin is racemic, but the enantiomers are not equipotent. In fact, (S)-warfarin is at least fourfold more potent as an anticoagulant than the (R)-warfarin. The difference in the activities and metabolism of the enantiomers is the key to understanding several stereoselective drug interactions. Similar stereochemical properties are noted for the other asymmetric coumarins (Fig. 31.5). In the case of acenocoumarol, the (R)-isomer is responsible for the majority of its activity. 

Figure 11.7 Some predicted sites of metabolism for M445526, tramadol and acenocoumarol.

The 4-hydroxycomnarins undergo biotransformation similar to warfarin, forming hydroxylated metabolites at the 6 and 7 positions. These hydroxylated metabolites accoimt for 63 to 99% of the metabolic clearance of 4-hydroxycoumarins, including acenocoumarol. The metabolic clearances of R- and S-acenocoumarol are 6 and 66 times higher than those of R- and S-warfarin, respectively [68]. The metabolism of acenocoumarol is also stereoselective in favor of the S enantiomer. Sulphaphenazole competitively inhibits the 7-hydroxylation of R- and S-acenocoumarol and the 6-hydroxylation of S-acenocoumarol. Omeprazole acts as a partial inhibitor of 6- and 7-hydroxylation of acenocoumarol enantiomers [68]. 

Acenocoumarol Piroxicam R t S Reduced metabolic clearance of R enantiomer t 79... 

Beyond those in vivo examples depicted in Table 4, there are some in vitro data suggesting stereoselective drug interactions with oral anticoagulants. For example, Hermans and Thijssen [68] investigated the potential of metabolic interactions in vitro between warfarin or acenocou-marol and cimetidine, propafenone, sulphaphenazole, or omeprazole using human liver microsomes. Sulphaphenazole competitively inhibited the 7- and in some experiments the 6-hydroxylation of S-warfarin and R- and S-acenocoumarol. Omeprazole partly inhibited the 6- and 7-hydroxylation of R-warfarin, R-acenocoumarol, and S-acenocoumarol [68]. 

Hermans, J.J. Thijssen, H.H. Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol P450 isozyme diversity determines the differences in their pharmacokinetics. Br. J. Pharmacol. 1993, 110, 482-490. 

Erythromycin is a known inhibitor of the cytochrome P450 isoenzyme CYP3A4. However, this isoenzyme has only a minor role in the metabolism of warfarin , (p.358), specifically the less active R-isomer of warfarin. Consequently, only minor increases in the levels of warfarin have been seen in pharmacokinetic studies, which would generally not be expected to be clinically relevant. However, it is possible that even these small changes might be important in a very few patients, particularly those with a low prothrombin complex aetivity. Other macrolides (azithromycin, clarithromycin, dirithromycin, roxithromycin) have less effect on CYP3A4 than erythromycin, and consequently would be expected to have even less effect on the pharmacokinetics of warfarin or acenocoumarol, which is borne out in the few studies available. Nevertheless, cases of interactions have been reported for nearly all these macrolides. Moreover, one cohort study found that clarithromycin increased the risk of an interaction and erythromycin did not. It is possible that there is some other, as yet unidentified, mechanism involved. Alternatively, it is equally possible that the relatively few cases just represent idiosyncratic effects attributable to other factors, and not to any interaction (see also Coumarins -i- Antibacterials , p.365). 

Co-trimoxazole modesitly inhibits the metabolism of A warfarin, and a number of case reports show that the anticoagulant effects of the coumarins warfarin, acenocoumarol, and phenprocoumon are increased by co-trimoxazole. Case reports surest that sul-fafurazole, sulfadoxine, and sulfamethizole may have similar effects. Two cohort studies have suggested that trimethoprim alone is associated with an increased risk of overanticoagulation, but this was less than that for co-trimoxazole in one of these studies. Anecdotal evidence su ests that the indanedione phenindione might not interact with co-trimoxazole, but in one study sul-faphenazole increased the effect of phenindione. 

It seems possible that ticlopidine inhibits the metabolism of R-warfarin, but the interaction with acenocoumarol is not understood. Ticlopidine alone can cause raised liver enzymes and cholestatic hepatitis, and whether these cases represent an interaction is unclear. 

Fluconazole cau e a dose-related inhibition of the metabolism of warfarin, and increases its anticoagulant effect. Cases of minor to major bleeding have been reported. There is one case report with acenocoumarol and fluconazole. 

In rate, ketoconazole potentiated the anticoagulant eflect of acenocoumarol, but at much higher doses than miconazole , (p.388). It is now known that ketoconazole is an inhibitor of the cytochrome P450 isoenzyme CYP3A4, but this isoenzyme has only a minor role in the metabolism of warfarin (p.358), specifically the less active R-isomer. 

Benzbromarone selectively inhibits the metabolism of S-warfarin by the cytochrome P450 isoenzyme CYP2C9 so that its effects are increased. The metabolism of the 7 -warfarin remains unchanged. Acenocoumarol and phenprocoumon are also known to be metabolised by CYP2C9, and would therefore be expected to interact similarly. Benziodarone is another ben-zofuran derivative with a similar structure to benzbromarone, and therefore probably interacts via a similar mechanism. 

Although in one early report, chlorpromazine 40 to 100 mg daily was said to have slightly sensitised 2 out of 8 patients to the effects of acenocoumarol and in another was reported to increase its anticoagulant effects in animals, there appears to be nothing else published to suggest that an interaction occurs. In vitro study in human liver microsomes found that chlorpromazine did not inhibit CYP2C9, the cytochrome P450 isoenzyme predominantly involved in the metabolism of warfarin , (p.358) and other coumarins. No eoumarin dose adjustments would therefore be anticipated to be needed on eoneurrent use. 

Unknown. Changes in the production of blood clotting factors and an increase in the affinity of warfarin for its site of action have been proposed. A study in guinea pigs using acenocoumarol suggested that changes in warfarin metabolism or its absorption from the gut are not responsible. ... 

The interaction between acenocoumarol and ivermectin with methidathion is not understood. When used on its own, ivermectin used for onchocerciasis normally has no effect on prothrombin times, but two unexplained cases of prolonged prothrombin times associated with the development of haematomas have been reported. Methidathion is an organophosphate. Lindane and other chlorinated hydrocarbon insecticides are known liver enzyme inducers, which increase the metabolism and clearance of the warfarin, thereby reducing or even abolishing its effects. 

Rofecoxib possibly inhibits the metabolism of the less active R-warfarin via inhibition of CYP1A2, and the active R-acenocoumarol by the same isoenzyme and CYP2C19. ... 

Piroxicam inhibits the metabolism of the active J -acenocoumarol, but its effect on the metabolism of warfarin is unknown. Lomoxicam inhibited the metabolism of warfarin, but not acenocoumarol, in vitro In addition NSAIDs have antiplatelet effects, which can prolong bleeding if it occurs. They may also cause gastrointestinal toxicity. Because of these effects, in patients taking anticoagulants, the risk of bleeding is increased by NSAIDs , (p.427). 

The two cases of interactions are unexplained. It is not obvious why dividing the acenocoumarol dose, or using ranitidine, would have reversed an interaction. No interaction via inhibition of coumarin metabolism is likely. Sildenafll alone appears to commonly cause nosebleeds in patients with pulmonary hypertension. ... 

Not understood. One suggestion is that the tricyclic antidepressants inhibit the metabolism of the anticoagulant (seen in animals with nortriptyline or amitriptyline and warfarin, but not with desipramine and acenocoumarol ), but tricyclics are not established known inhibitors of the metabolism of any drug so this seems unlikely. Another idea is that the tricyclics slow gastrointestinal motility thereby increasing the time available for the dissolution and absorption of dicoumarol. ... 

Acenocoumarol, warfarin and ciclosporin are all metabolised, at least in part, by the cytochrome P450 isoenzyme CYP3A4. It is possible that some competition occurs for metabolism, leading to increased or decreased effects of the anticoagulants and decreased ciclosporin levels. 

Another example is represented by the anticoagulant acenocoumarol which is metabolized in human body mainly by CYP2C9 through hydroxylations at the C6, C7, and C8 positions at a ratio of 0.9 1 0.1 (61). The pharmacological activity of this drug resides mainly in the (i )-form. (P)-Acenocoumarol has also been found to be metabolized by CYP1A2 via C6-hydroxylation and by CYP2C19 via hydroxylations at the C6, C7, and C8 positions (Scheme 5.16). 

Hydroxy-(R)-acenocoumarol 8-Hydroxy-(R)-acenocoumarol Scheme 5.16 Metabolism of acenocoumarol by different hydroxylations. 

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