DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

862 with the functional level of prothrombin, and to a lesser extent,
factor X (Zivelin et al., 1993).
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Dosage. The usual adult dosage of warfarin is 2-5 mg/day
for 2-4 days, followed by 1-10 mg/day as indicated by
measurements of the international normalized ratio
(INR), a value derived from the patient’s PT (see the functional
definition of INR in the section on “Laboratory
Monitoring”). As indicated later, common genetic polymorphisms
render patients more or less sensitive to warfarin.
A lower initial dose should be given to patients with
an increased risk of bleeding, including the elderly.
Warfarin usually is administered orally; age correlates
with increased sensitivity to the drug. Warfarin also can be
given intravenously without modification of the dose.
Intramuscular injection is not recommended because of
the risk of hematoma formation.
Absorption. The bioavailability of warfarin is nearly
complete when the drug is administered orally, intravenously,
or rectally. Bleeding has occurred from
repeated skin contact with solutions of warfarin used
as a rodenticide. However, different commercial preparations
of warfarin tablets vary in their rate of dissolution,
and this causes some variation in the rate and
extent of absorption. Food in the GI tract also can
decrease the rate of absorption. Warfarin usually is
detectable in plasma within 1 hour of its oral administration,
and concentrations peak in 2-8 hours.
Distribution. Warfarin is almost completely (99%)
bound to plasma proteins, principally albumin, and the
drug distributes rapidly into a volume equivalent to the
albumin space (0.14 L/kg). Concentrations in fetal
plasma approach the maternal values, but active warfarin
is not found in milk (unlike other coumarins and
indandiones). Therefore, warfarin can safely be administered
to nursing mothers.
Biotransformation and Elimination. Warfarin is administered
as a racemic mixture of S- and R-warfarin. S-warfarin
is 3-5 fold more potent than R-warfarin and is
metabolized principally by CYP2C9. Inactive metabolites
of warfarin are excreted in urine and stool. The average
rate of clearance from plasma is 0.045 mL/min –1. kg –1 .
The t 1/2
varies (25-60 hours), with a mean of ~40 hours;
the duration of action of warfarin is 2-5 days.
Polymorphisms in two genes, CYP2C9 and VKORC1 (vitamin K
epoxide reductase complex, subunit 1) account for most of the
genetic contribution to the variability in warfarin response. CYP2C9
variants affect warfarin pharmacokinetics, whereas VKORC1 variants
affect warfarin pharmacodynamics. Common variations in the CYP2C9
gene (designated CYP2C9*2 and *3), encode an enzyme with
decreased activity, and thus are associated with higher drug concentrations
and reduced warfarin dose requirements. At least one variant
allele of CYP2C9*2 or CYP2C9*3 is present in ~25% of European-
Americans, but these variants are relatively uncommon in African-
American and Asian populations (Table 30–2). Heterozygosity for
CYP2C9*2 or *3 decreases the dose of warfarin required for anticoagulation
by approximately 20-30% compared with “wild type” individuals
(CYP2C9*1/*1). Homozygosity for CYP2C9*2 or *3 can decrease
the warfarin dose requirement by approximately 50-70%. Generally,
the *3 allele has a greater effect than the *2 allele.
Consistent with decreased warfarin dose requirements, subjects
who carry at least one copy of a CYP2C9 variant allele appear
to have an increased risk of bleeding. Thus, compared with individuals
with no variant alleles, carriers of CYP2C9*2 and CYP2C9*3
have relative risks of bleeding of 1.91 and 1.77, respectively.
VKORC1 reduces vitamin K epoxide to vitamin K hydroquinone
(see Figure 30–7) and is the target of coumarin anticoagulants,
such as warfarin. Several genetic variations in VKORC1 are in
strong linkage disequilibrium and have been designated haplotypes
A and B (or non-A). VKORC1 variants are more prevalent than those
of CYP2C9. The prevalence of VKORC1 genetic variants is higher in
Asians, followed by European-Americans and African-Americans.
Polymorphism in VKORC1 explains ~30% of the variability in warfarin
dose requirements. Compared with VKORC1 non-A/non-A
homozygotes, the warfarin dose requirement is decreased by ~25%
in heterozygotes and ~50% in A/A homozygotes.
The clinical relevance of these genetic polymorphisms
remains uncertain. The goal of warfarin therapy is to maintain a
patient within a target INR range, most often an INR value between
2 and 3. The risk of serious bleeding increases with INR values >4
and is highest during initiation of warfarin therapy. Variations in
VKORC1 have a greater effect than CYP2C9 variants on warfarin
responses early in therapy. Patients with VKORC1 haplotype A have
significantly higher INR values in the first week of warfarin therapy
than non-A homozygotes; those with one or two VKORC1 haplotype
A alleles achieve a therapeutic INR more rapidly and are more
likely to have an INR >4 than patients with two non-A alleles. Both
the VKORC1 haplotype and CYP2C9 genotype have a significant
effect on the warfarin dose after the first 2 weeks of therapy.
Based on evidence that genetic variations affect warfarin dose
requirements and responses to therapy, the FDA amended the prescribing
information for warfarin in 2007 to indicate that lower warfarin
initiation doses be considered for patients with CYP2C9 and VKORC1
genetic variations. Efforts to facilitate the rational incorporation of
genetic information into patient care have included the development
of a warfarin dosing algorithm and point-of-care methods for CYP2C9
and VKORC1 genotyping. In a study of more than 4000 patients, the
International Warfarin Pharmacogenetics Consortium (2009) compared
the accuracy of a pharmacogenetic algorithm that included
VKORC1 and CYP2C9 genotypes with two conventional clinical
approaches: one based on clinical information to adjust the initial
dose, and the other using a fixed-dose approach. The pharmacogenetic
algorithm predicted the warfarin dose significantly better than
the other two approaches. Moreover, the pharmacogenetic algorithm
significantly improved the dose prediction for patients who required
either high or low doses of warfarin (<21 mg/week or >49 mg/week).
Genetic variation clearly affects warfarin dose requirements
and predilection to toxicity. Table 30–2 summarizes the effect of