BIOTRANSFORMATION OF DRUGS

WarfarinCoumadin® the most common

anticoagulant drug

By

ALAGAR . S

M.Tech/Computational Biology

Background

In the early 20th century, bis-hydroxycoumarin

(dicumarol) was discovered after cows livestock

had eaten spoiled Sweet clover and died of a

hemorrhagic disease.

Today, coumarin derivatives are used

therapeutically as anticoagulants and commercially

as rodenticides. Warfarin is the most common oral

anticoagulant used today.

Approximately 2 million people in the U.S. start

taking warfarin each year.

What is Warfarin?

Warfarin is an oral coumarin anticoagulant widely

used to control and prevent thromboembolic

disorders.

Warfarin is clinically available as a racemic mixture

of R- and S-warfarin. The S-enantiomer has 3–5

times greater anticoagulation potency than its

optical congener R-warfarin.

Mechanism of Action

Warfarin acts by antagonizing the antihemorrhagic

effect of vitamin K.

It inhibits hepatic synthesis of vitamin K dependent

coagulation factors II, VII, IX, and X by inhibiting

vitamin K1 -2,3 epoxide reductase, preventing

vitamin K from being reduced to its active form.

Vitamin K is an essential cofactor for post-

translational carboxylation of glutamate

residues on the N-terminus regions of vitamin

K-dependent proteins to gamma-carboxy-

glutamates

Mechanism of Action

Decarboxyprothrombin is converted to prothrombin by

carboxylation of glutamate residues to gamma-

carboxyglutamate

–By inhibiting vitamin K epoxide reductase and vitamin K reductase, warfarin leads to the accumulation of vitamin K epoxide in the liver and plasma and the depletion of reduced vitamin K (active form, KH2)

–Reduced vitamin K is necessary for carboxylation of glutamate residues

–Decrease in KH2 limits the gamma-carboxylation of vitamin K dependent coagulant proteins -

–Prothrombin (Factor II) Factors VII, IX, X Protein C and Protein S

Wafarinblocks

Vitamin Kepoxide

reductase

Vitamin Kreductase

blocked byWarfar in

Factor II(10 g lutamic

res idues)

C H 2 -C H 2 C O O -

CarboxylatedFactor II

C H 2 - C H

C O O -

C O O -

CO2

OH

OH

CH3

R

O2

O

O

O

CH3

R

ReducedVitamin K

(act ive)

Epoxide formVitamin K(inact ive)

Pr o t e i nc a r b o x y l a se

T hi o lC o f a c t o r

Pharmacokinetic

The oral bioavailability of warfarin is nearly 100%.

It is highly bound (approximately 99%) to plasma

protein, mainly albumin. (The high degree of protein binding is

one of several mechanisms whereby other drugs interact with warfarin)

Warfarin is distributed to the liver, lungs, spleen,

and kidneys. It does not appear to be distributed to

breast milk in significant amounts. It crosses the

placenta and is a known teratogen.

The duration of anticoagulant effect after a single

dose of warfarin is usually 5-7 days.

Pharmacokinetic (cont’d)

Warfarin is metabolized by hepatic cytochrome

P-450 (CYP) isoenzymes to inactive metabolites,

which are excreted in the bile. (It also is metabolized by

reductases to reduced metabolites “warfarin alcohols” , which are excreted in

the kidneys).

Warfarin metabolism may be altered in the

presence of hepatic dysfunction or advanced age

but is not affected by renal impairment.

Warfarin Monitoring

Prothrombin time (PT) — The most commonly used

test to measure the effect of warfarin. It measures

the time it takes for the clotting mechanism to

progress. Normal range (12–15 seconds).

International Normalized Ratio (INR) — The INR is a way

of expressing the PT in a standardized way; this ensures that results obtained

by different laboratories can be reliably compared.

• The longer it takes the blood to clot, the higher the

PT and INR. In most cases the target INR range

will be 2 to 3, although other ranges may be chosen

if there are special circumstances.

PHASE-1 METABOLISM

PHASE-1 METABOLISM

PHASE-1 METABOLISM

. Kinetic profiles for the formation of each product of the reactions are as

follows: squares () for 6-hydroxywarfarin, triangles (▴) for 7-

hydroxywarfarin, inverted triangles (▾) for 8-hydroxywarfarin, and

diamonds (◆) for 4′-hydroxywarfarin. Reported values represent

three experiments performed in duplicate. Data were fit to the

Michaelis-Menten mechanism using GraphPad Prism 5® software

(La Jolla, CA)

PHASE-2 METABOLISM

Glucuronidation of Warfarin Metabolites

PHASE-2 METABOLISM

Excretion of metabolites through Bile(P-

Glycoprotein transporters) and urine

TOXICITY

Hemorrhaging

Warfarin induced skin necrosis

Drug interactions

Teratogen in pregnant women

OVER DOSE TREATMENT

Stop taking warfarin

Vitamin K1 treatment in excess dose

Fresh frozen plasma with vitaminK1

References

Katzung PHARMACOLOGY, 9e > Drugs Used in

Disorders of Coagulation

emedicine.medscape.com>Toxicity, Warfarin and

Superwarfarins, Warfarin Pharmacogenetics.

drugs.com/pro/warfarin

uptodate.com>Patient information: Warfarin

Drug Metab Lett. 2012 September 1; 6(3): 157–164

The journal of pharmacology and experimental

therauputics Vol. 324, No. 1 129858/3285451

JPET 324:139–148, 2008