bio transformation of warfarin
TRANSCRIPT
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
. 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)
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