Acenocoumarol Liver

P. H. Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metah. Disp. 2000,... 

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. 

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. 

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. 

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. 

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