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Agents that DECREASE metabolism (inhibit or compete for cytochrome P450)
are more important than those that increase metabolism
Drug X R-warfarin andS-warfarin
Must also consider that both forms ofwarfarin can interact with other drugs
DRUG INTERACTIONSDrug X S-warfarin
DRUG INTERACTIONS
PHARMACOKINETIC• ABSORPTION
binding in intestine
• DISTRIBUTION plasma protein binding
• ELIMINATIONcytP450 inhibition
cytP450 induction
Drug X S-warfarin
DRUG INTERACTIONS
PHARMACODYNAMIC• SYNERGISM
platelet/clotting factor function
• ANTAGONISM concentration of clotting
factors
• ALTERED VITAMIN K availability of vitamin K
Drug X S-warfarin
Both inhibitors and substrates of a particular CYP isozyme decrease the metabolism of substrates of that isozyme increased efficacy
Inducers increase the metabolism of substrates decreased efficacy
For example, for CYP 2C9, both amiodarone and carvedilol will increase the efficacy of celecoxib, but barbiturates will reduce it
In other words, drugs in the inhibitor and inducer columns can affect drugs in the substrate column, but substrates don’t affect inhibitors and inducers
Substrates can affect other substrates
Taking up the case of warfarin, the active enantiomer is S-warfarin which is metabolized by CYP 2C9.
That means we have to be most concerned by drugs that inhibit CYP 2C9 ---- i.e., amiodarone, cimetidine, etc., and especially fluvoxamine.
Drug X S-warfarin
Drug X R&S-warfarin
We also have to worry about drug interactions where warfarin causes an adverse drug interaction with another drug.
Neither warfarin enantiomer is an inducer or an inhibitor of CYP enzymes. So the drugs that could interact are ones that are substrates for the CYP isozymes that EITHER R- or S-warfarin is a substrate of. So you could expect interactions with amitriptyline, carvedilol, amitriptyline and alfentanil (reading just the first drug in the substrate list for each affected isozyme)