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

1702 de novo purine synthesis and also become incorporated
into nucleic acids. The structural formula of 6-MP and
other purine analogs is shown in Figure 61–11.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Mechanism of Action. Both 6-TG and 6-MP are excellent substrates
for hypoxanthine guanine phosphoribosyl transferase (HGPRT) and
are converted in a single step to the ribonucleotides 6-thioguanosine-
5′-monophosphate (6-thioGMP) and 6-thioinosine-5′-monophosphate
(T-IMP), respectively. Because T-IMP is a poor substrate for
guanylyl kinase, the enzyme that converts guanosine monophosphate
(GMP) to guanosine diphosphate (GDP), T-IMP accumulates intracellularly
and in a second step is converted to 6-TGMP. T-IMP inhibits
the new formation of ribosyl-5-phosphate, as well as conversion of
inosine-5′-monophosphate (IMP) to adenine and guanine nucleotides.
Of these, the most important point of attack seems to be the reaction
of glutamine and PRPP to form ribosyl-5-phosphate, the first committed
step in the de novo pathway. 6-Thioguanine nucleotide is incorporated
into DNA, where it induces strand breaks and base mispairing.
Strand breaks depend on the presence of an intact MMR system, the
absence of which leads to resistance.
Mechanisms of Resistance to the Thiopurine Antimetabolites.
The most common mechanism of 6-MP resistance observed in vitro
is deficiency or complete lack of the activating enzyme, HGPRT, or
increased alkaline phosphate activity. Other mechanisms for resistance
include 1) decreased drug uptake, or increased efflux due to
one of several active transporters; 2) alteration in allosteric inhibition
of ribosylamine 5-phosphate synthase; and 3) impaired recognition of
DNA breaks and mismatches due to loss of a component (MSH6) of
MMR (Karran and Attard, 2008; Cahill et al., 2007).
Mercaptopurine Pharmacokinetics and Toxicity. Absorption of mercaptopurine
is incomplete (10-50%) after oral ingestion; the drug is
subject to first-pass metabolism by xanthine oxidase in the liver.
Food or oral antibiotics decrease absorption. Oral bioavailability is
increased when mercaptopurine is combined with high-dose
methotrexate.
After an intravenous dose, the t 1/2
of the drug in plasma is relatively
short (~50 minutes in adults), due to rapid metabolic degradation
by xanthine oxidase and by thiopurine methyltransferase
(TPMT). Restricted brain distribution of mercaptopurine results
from an efficient efflux transport system in the blood-brain barrier.
In addition to the HGPRT-catalyzed anabolism of mercaptopurine,
there are two other pathways for its metabolism. The first involves
methylation of the sulfhydryl group and subsequent oxidation of the
methylated derivatives. Activity of the enzyme TPMT reflects the
inheritance of polymorphic alleles; up to 15% of the Caucasian population
has decreased enzyme activity. Low levels of erythrocyte
TPMT activity are associated with increased drug toxicity in individual
patients and a lower risk of relapse (Pui et al., 2004). In patients
with auto-immune disease treated with mercaptopurine, those with
polymorphic alleles may experience bone marrow aplasia and lifethreatening
toxicity. Testing for these polymorphisms prior to treatment
is recommended in this patient population.
High concentrations of 6-methylmercaptopurine nucleotides
are formed in white blood cells and bone marrow following 6-MP
administration. They are less potent than 6-MP nucleotides as metabolic
inhibitors, and their significance in contributing to the activity
of 6-MP is not known.
A relatively large percentage of the administered sulfur
appears in the urine as inorganic sulfate, the result of enzymatic
desulfuration. The second major pathway for 6-MP metabolism
involves its oxidation by xanthine oxidase to 6-thiouric acid, an inactive
metabolite. Oral doses of 6-MP should be reduced by 75% in
patients receiving the xanthine oxidase inhibitor, allopurinol. No
dose adjustment is required for intravenous dosing.
Therapeutic Uses. In the maintenance therapy of ALL, the initial
daily oral dose of mercaptopurine (6-MP; PURINETHOL, others) is
50-100 mg/m 2 and is thereafter adjusted according to white blood
cell and platelet count. The combination of methotrexate and 6-MP
appears to be synergistic. By inhibiting the earliest steps in purine
synthesis, methotrexate elevates the intracellular concentration of
PRPP, a cofactor required for 6-MP activation.
Clinical Toxicities. The principal toxicity of 6-MP is bone marrow
depression, although in general, this side effect develops more gradually
than with folic acid antagonists; accordingly, thrombocytopenia,
granulocytopenia, or anemia may not become apparent for
several weeks. When depression of normal bone marrow elements
occurs, dose reduction usually results in prompt recovery, although
myelosuppression may be severe and prolonged in patients with a
polymorphism affecting TPMT. Anorexia, nausea, or vomiting is
seen in ~25% of adults, but stomatitis and diarrhea are rare; manifestations
of GI effects are less frequent in children than in adults.
Jaundice and hepatic enzyme elevations occur in up to one-third of
adult patients treated with 6-MP and usually resolve upon discontinuation
of therapy. Their appearance has been associated with bile
stasis and hepatic necrosis on biopsy. 6-MP and its derivative, azathioprine,
predispose to opportunistic infection such as reactivation
of hepatitis B, fungal infection, and Pneumocystis pneumonia and
an increased incidence of squamous cell malignancies of the skin. 6-
MP has teratogenic effects during the first trimester of pregnancy,
and AML has been reported after prolonged 6-MP therapy for
Crohn’s disease (Heizer and Peterson, 1998).
Fludarabine Phosphate
This compound is a fluorinated, deamination-resistant,
phosphorylated analog of the antiviral agent vidarabine
(9-β-D-arabinofuranosyl-adenine). It is active in CLL
and low-grade lymphomas. It has found important uses
as a cytotoxic drug and as a potent immunosuppressant.
HO
O
P
OH
F
O
N
C
N
HO
NH 2
O
N
N
FLUDARABINE PHOSPHATE
OH