Warfarin Donepezil

Only a small number of drug interactions have been reported with donepezil. In vitro studies show a low rate of binding of donepezil to cytochrome P-450 (CYP)3A4 or 2D6. Whether or not donepezil has the potential for enzyme induction is not known. No interactions with theophylline, cimeti-dine, warfarin, digoxin, or ketoconazole have been documented. In vitro studies show that inhibitors of CYP3A4 and 2D6 have the potential to inhibit the metabolism of donepezil. The clinical relevance of this is unknown. However, monitoring for possible increased peripheral side effects is advised... 

Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Three of the human metabolites of donepezil have not undergone extensive safety tests in animals. These comprise two O-demethylated derivatives and an N-oxidation product. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. The rate of metabolism of donepezil is slow and does not appear to be saturable. These findings are consistent with the results from formal pharmacokinetic studies which showed that donepezil and/or its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine, or digoxin... 

In vitro plasma protein binding of donepezil is 96%, mainly to albumin (75%). Plasma protein binding competition with furosemide, digoxin and warfarin showed that... 

Donepezil, galantamine, rivastigmine and tacrine do not appear to alter the pharmacokinetics or effects of warfarin. 

In an open-label, erossover study, 12 healthy men were given donepezil 10 mg daily for 19 days with a single 25-mg dose of warfarin on day 14. The pharmaeokineties of R- and S-warfarin and the prothrombin times were unehanged by the presenee of the donepezil, and vital signs, ECG and laboratory tests were unaltered. ... 

Tiseo PJ, Foley K, Friedhoff LT. The effect of multiple doses of donepezil hydrochiccide on the pharmacokinetic and pharmacoitynamic profile of warfarin. BrJClin Pharmacol (1998) 46 (Suppl 1), 45-50. 

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