warfarin

Mechanism of action

The diagram shows that vitamin K must be reduced for the carboxylation of the vitamin K–dependent clotting factors (II, VII, IX, and X). After this carboxylation step, vitamin K becomes oxidized. The enzyme vitamin K epoxide reductase (encoded by the VKORC1 gene) must then be recycled back to its reduced form.

Warfarin functions by blocking vitamin K epoxide reductase. As a result, the enzyme cannot convert oxidized vitamin K back into its reduced form, decreasing the availability of reduced vitamin K for the carboxylation of clotting factors.

As a result, the newly synthesized clotting factors II, VII, IX, and X are inadequately carboxylated and exhibit reduced activity, contributing to warfarin's anticoagulant effect.

Warfarin is administered as a racemic mixture of two enantiomers: S-warfarin and R-warfarin. Although both enantiomers have anticoagulant activity, S-warfarin is about three to five times more potent than R-warfarin in blocking vitamin K epoxide reductase.

S-warfarin is primarily metabolized in the liver by the CYP2C9 enzyme.
R-warfarin is metabolized by several different CYP isoforms, especially CYP1A2, CYP1A1, and CYP3A4.

Differences in the metabolism (and thus clearance) of these enantiomers can affect warfarin therapy's overall efficacy and dosing requirements.

Genetic polymorphism

For warfarin therapy, two major genetic polymorphisms of clinical importance are:

VKORC1 (Vitamin K Epoxide Reductase Complex Subunit 1)

VKORC1 is the target enzyme of warfarin. Certain genetic variants (haplotypes) reduce or increase this enzyme’s sensitivity to warfarin:
- “Sensitive” variants (e.g., VKORC1 -1639G>A): Patients often need lower doses because the A allele (or the "A haplotype") produces less VKORC1, and lower warfarin doses are required to inhibit VKORC1.
- “Resistant” variants: Patients may need higher doses because their enzyme is less susceptible to warfarin’s inhibitory effect.

CYP2C9

S-warfarin (the more potent enantiomer) is metabolized predominantly by CYP2C9. Polymorphisms (like CYP2C9*2 or *3) can lead to reduced enzyme activity, slowing the breakdown of S-warfarin:

CYP2C9*2 reduces warfarin metabolism by 30%
CYP2C9*3 reduces warfarin metabolism by 90%.
CYP2C9*1 metabolizes warfarin normally

Dietary Factors

Warfarin interferes with the recycling of vitamin K. If an individual's diet is rich in vitamin K, such as leafy green vegetables and certain supplements, they may require a higher dose of warfarin.

Diets that increase INR values.

Garlic

Ginger

Turmeric

Fish oil, vitamin E

Mangosteen

papaya

Mango

Diets that decrease INR values.

green vegetable

Carrot

Soy bean

Banana

Green tea

sea weed

coenzyme Q10

Berries

Ginseng

Avocado

Orange

Kiwi

Drug-drug interaction

Common Pharmacokinetic Interactions and Proposed Mechanisms

Drugs that increase INR values.

CYP3A4 inhibitors
allopurinol
alprazolam
amiodarone
amlodipine
amprenavir
aprepitant
atazanavir
atorvastatin
azithromycin
bicalutamide
chloramphenicol
chlorpromazine
cilostazol
cimetidine
ciprofloxacin
clarithromycin
conivaptan
cyclosporine
darunavir/ritonavir
dasatinib
delaviridine
diltiazem
dronedarone
erythromycin
fluconazole
fluoxetine
fluvoxamine
fosamprenavir
gatifloxacin
grapefruit
imatinib
indinavir
isavuconazole
isoniazid
itraconazole
ketoconazole
levofloxacin
lopinavir/ritonavir
nefazodone
nelfinavir
nifedipine
nilotinib
norfloxacin
oral contraceptives
posaconazole
ranitidine
ranolazine
ritonavir
saquinavir
sodium valproate
tamoxifen
telithromycin
tipranavir
verapamil
voriconazole
zileuton

CYP1A2 inhibitors
acyclovir
allopurinol
amiodarone
cimetidine
ciprofloxacin
clarithromycin
diltiazem
disulfiram
duloxetine
efavirenz
enoxacin
erythromycin
famotidine
fluvoxamine
gatifloxacin
grapefruit
isoniazid
ketoconazole
levofloxacin
methoxsalen
mexiletine
norfloxacin
oral contraceptives
peginterferon-alfa-2a
phenylpropanolamine
piperine
propafenone
propranolol
rhytomycin
rofecoxib
terbinafine
thiabendazole
ticlopidine
tolfenamic acid
troleandomycin
verapamil
zafirlukast
zileuton

CYP2C9 inhibitors
amiodarone
capecitabine
cotrimoxazole
etravirine
fluconazole
fluvastatin
fluvoxamine
metronidazole
miconazole
oxandrolone
sulfinpyrazone
tigecycline
voriconazole
zafirlukast

Drugs that decrease INR values.

CYP3A4 inducers
amprenavir
armodafinil
bosentan
carbamazepine
dexamethasone
efavirenz
eslicarbazepine
etravirine
fosphenytoin
hydrocortisone
lumakaftor
lumakaftor-ivakaftor
modafinil
nafcillin
nevirapine
omeprazole
oxcabazepine
phenobarbital
phenytoin
pioglitazone
prednisolone
primidone
rifabutin
rifampicin
rifapentin
rufinamide
st. john's wort
zonisamide

CYP1A2 inducers
antipyrine
caffeine
carbamazepine
cigarette smoking
insulin
lansoprazole
montelukast
moricizine
nafcillin
nelfinavir
omeprazole
pentobarbital
phenobarbital
phenytoin
primaquine
rifampicin
ritonavir
secobarbital
sulfinpyrazone
teriflunomide

CYP2C9 inducers