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

sometimes resulting in colicky abdominal pain and
obstruction, may be prevented by a prophylactic program
of laxatives and hydrophilic (bulk-forming) agents and
usually is a problem only with doses >2 mg/m 2 .
Alopecia occurs in ~20% of patients given vincristine;
however, the alopecia is always reversible,
frequently without cessation of therapy. Modest
leukopenia may follow vincristine administration.
Thrombocytopenia, anemia, GI cholic and obstipation,
and the syndrome of inappropriate secretion of
antidiuretic hormone are less common adverse effects.
Inadvertent injection of vincristine into the CSF causes
a devastating and often fatal irreversible coma and
seizures (Williams et al., 1983). CSF exchange has
averted a fatal outcome in anecdotal reports.
Vinorelbine
Vinorelbine (NAVELBINE, others) is administered in normal
saline as an intravenous infusion over 6-10 minutes.
When used alone, it is given at doses of 30 mg/m 2
either weekly or for 2 out of every 3 weeks. When used
with cisplatin for the treatment of non–small cell lung
cancer, it is given at doses of 25 mg/m 2 either weekly or
for 3 out of every 4 weeks. A lower dose (20-25 mg/m 2 )
may be required for patients who have received prior
chemotherapy, and dosage adjustment is necessary for
hematological toxicity. Its primary toxicity is granulocytopenia,
with only modest thrombocytopenia and less
neurotoxicity than other vinca alkaloids. Vinorelbine
may cause allergic reactions and mild, reversible
changes in liver enzymes. An oral formulation of
vinorelbine is active in non–small cell lung carcinoma,
and phase III studies are ongoing (Krzakowski et al.,
2008). Similar to the other vincas, doses should be
reduced by 50% or 75% in patients with plasma bilirubin
2.1-3 mg/dL or >3 mg/dL, respectively.
TAXANES
The first compound of this series, paclitaxel (TAXOL,
others), was isolated from the bark of the Western yew
tree in 1971 and presented significant problems in formulation
because of its poor aqueous solubility. It was
reformulated and approved by the U.S. Food and Drug
Administration (FDA) in 2005 as an albumin-bound
nanoparticle solution for infusion (nab-paclitaxel,
ABRAXANE). Paclitaxel and its congenic, the semisynthetic
docetaxel (TAXOTERE), exhibit unique pharmacological
properties as inhibitors of mitosis, differing
from the vinca alkaloids and colchicine derivatives in
that they bind to a different β-tubulin site and promote
rather than inhibit microtubule formation. The taxanes
have a central role in the therapy of ovarian, breast,
lung, GI, genitourinary, and head and neck cancers
(Rowinsky and Donehower, 1995).
Chemistry. Paclitaxel is a diterpenoid compound that contains a
complex eight-member taxane ring as its nucleus (Figure 61–12).
The side chain linked to the taxane ring at C13 is essential for its
antitumor activity. Modification of the side chain has led to identification
of the more potent analog, docetaxel (Figure 61–12),
which shares the same spectrum of clinical activity as paclitaxel,
but differs in its toxicity. Originally purified as the parent molecule
from yew bark, paclitaxel now can be obtained for commercial
purposes by semisynthesis from 10-desacetylbaccatin, a
precursor found in yew needles. It also has been successfully synthesized
(Nicolaou et al., 1994) in a complex series of reactions.
Paclitaxel has very limited water solubility and is administered in
a vehicle of 50% ethanol and 50% polyethoxylated castor oil (CRE-
MOPHOR EL); this vehicle likely is responsible for a high rate of
hypersensitivity reactions. Patients receiving this formulation are
protected by pretreatment with a histamine H 1
-receptor antagonist
such as diphenhydramine, an H 2
-receptor antagonist such as
cimetidine (see Chapter 32), and a glucocorticoid such as dexamethasone
(see Chapter 42).
Nab-paclitaxel is soluble in aqueous solutions and can be
administered safely without prophylactic antihistamines or steroids.
This form of paclitaxel has increased cellular uptake via an albuminspecific
mechanism.
Docetaxel, somewhat more soluble than paclitaxel, is administered
in polysorbate 80 and is associated with a lower incidence of
hypersensitivity reactions than paclitaxel dissolved in CREMOPHOR.
However, pretreatment with dexamethasone for 3 days starting 1 day
R 1 R 2
O R 2
R 1 N
O
CH 3 H
O O
H 3 C
O
CH 3
H CH OH
3
H OH HO
H
O
OCOCH 3
PACLITAXEL
DOCETAXEL
H 3 C
CH 3
C
CH 3
O
O
H 3 C
Figure 61–12. Chemical structures of paclitaxel and its more
potent analog, docetaxel.
H
O
O
C
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CHAPTER 61
CYTOTOXIC AGENTS