Inhibitor of zymogen synthesis: WARFARIN
DRUG INTERACTION THEORY
- there are currently >225 drugs that have clinically documented interactions with WARFARIN
- look up drug interactions in Epocrates (most common trade name: coumadin)
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with the exception of mifepristone (RU-486; an abortifacaent), the recommendation is to adjust the dose of WARFARIN, not to eliminate the concomittant use of multiple drugs
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although drug-drug interactions that involve other pharmacokinetic and pharmacodynamic processes are important, probably the most complicated interactions are those that involve CYP450 isozymes
- as a starting point, consider that there are two potential ways that a drug can interact with WARFARIN via CYP450:
- DRUG X affects S-WARFARIN
S is the active enantiomer, therefore the most important component to consider re. therapeutic index -
R&S-WARFARIN affects DRUG X
- DRUG X affects S-WARFARIN
- there are 3 ways that the drugs could interact via a specific CYP450 isozyme:
- being SUBSTRATES: drugs that are metabolized by the same isozymes will compete with each other for the binding site, resulting in increased serum concentrations of both drugs (decreased metabolism)
- S-WARFARIN is metabolized by CYP2C9
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R-WARFARIN is metabolized by CYP1A2, CYP2C19 and CYP3A4
- one drug functioning an INHIBITOR: the inhibiting drug is not metabolized, but decreases the activity of a specific isozyme, resulting in increased serum concentrations of the SUBSTRATE of that isozyme
- inhibitors of CYP2C9 are particularly critical because they increase the concentrations of S-WARFARIN
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CYP2C9 inhibitors include: amiodarone, cimetidine, cortrimoxazole, fluconazole, fluvoxamine, isoniazid, ketoconazole, metronidazole and zafirlukast
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one drug functioning as an INDUCER: the inducing drug is not metabolized, but increases the activity of a specific isozyme, resulting in decreased serum concentrations of SUBSTRATES of that isozyme
- being SUBSTRATES: drugs that are metabolized by the same isozymes will compete with each other for the binding site, resulting in increased serum concentrations of both drugs (decreased metabolism)
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neither enantiomer of WARFARIN induces or inhibits any CYP450 isozyme, therefore the only effect of WARFARIN on other drugs is to increase the plasma concentration of substrates of CYP2C9, CYP1A2, CYP2C19 or CYP3A4
- more advanced drug-drug interaction analyses (e.g., Tarascon Deluxe) include tables of CYP450 interactions, as summarized in these links: