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

1358 liver function tests also may be dose related. Although keeping drug
levels in the appropriate range diminishes these adverse effects, they
can occur even with therapeutic serum levels of 6-thioguanine
nucleotides. The serious adverse effect of cholestatic hepatitis is relatively
rare. Although the increased risk of infection is a significant
concern with immunosuppressives, especially if pancytopenia
occurs, infections are linked more closely to concomitant glucocorticoid
therapy than to the immunosuppressives (Aberra et al., 2003).
Immunosuppressive regimens given in the setting of cancer
chemotherapy or organ transplants have been associated with an
increased incidence of malignancy, particularly non- Hodgkin’s
lymphoma. Definitive conclusions about the causative roles of
azathioprine–mercaptopurine in lymphomas are complicated by the
possible increased incidence of lymphomas in IBD per se and by the
relative rarity of these cancers. The increased risk, if any, must be relatively
small.
SECTION VI
DRUGS AFFECTING GASTROINTESTINAL FUNCTION
Metabolism and Pharmacogenetics. Favorable responses
to azathioprine–mercaptopurine are seen in up to twothirds
of patients. Recent insights into the metabolism of
the thiopurine agents and appreciation of genetic polymorphisms
in these pathways have provided new insights
into variability in response rates and adverse effects. As
shown in Figure 47–4, mercaptopurine has three
metabolic fates:
• conversion by xanthine oxidase to 6-thiouric acid
• metabolism by thiopurine methyltransferase (TPMT)
to 6-methyl-mercaptopurine (6-MMP)
• conversion by hypoxanthine–guanine phosphoribosyl
transferase (HGPRT) to 6-thioguanine nucleotides and
other metabolites
The relative activities of these different pathways
may explain, in part, individual variations in efficacy and
adverse effects of these immunosuppressives.
The plasma t 1/2
of mercaptopurine is limited by its relatively
rapid (i.e., within 1-2 hours) uptake into erythrocytes and other tissues.
Following this uptake, differences in TPMT activity determine
the drug’s fate. Approximately 80% of the U.S. population has what
is considered “normal” metabolism, whereas 1 in 300 individuals
has minimal TPMT activity. In the latter setting, mercaptopurine
metabolism is shifted away from 6- methyl- mercaptopurine and
driven toward 6-thioguanine nucleotides, which can severely suppress
the bone marrow. About 10% of people have intermediate
TPMT activity; given a similar dose, these individuals will tend to
have higher 6-thioguanine levels than the normal metabolizers.
Finally, ~10% of the population is considered rapid metabolizers. In
these individuals, mercaptopurine is shunted away from 6-thioguanine
nucleotides toward 6-MMP, which has been associated with abnormal
liver function tests. In addition, relative to normal metabolizers,
the 6-thioguanine levels of these rapid metabolizers are lower for an
equivalent oral dose, possibly reducing therapeutic response. Given
this variability, some experts evaluate an individual’s TPMT activity
status prior to initiating treatment with thiopurines and also measure
6-thioguanine/6-MMP levels in individuals not responding to therapy.
To avoid these complexities, treatment with 6-thioguanine was
explored; unfortunately, 6-thioguanine is associated with a high incidence
of an uncommon liver abnormality, hepatic nodular regeneration,
and associated portal hypertension; 6-thioguanine therapy of
IBD therefore has been abandoned.
Xanthine oxidase in the small intestine and liver converts
mercaptopurine to thiouric acid, which is inactive as an immunosuppressant.
Inhibition of xanthine oxidase by allopurinol diverts mercaptopurine
to more active metabolites such as 6-thioguanine and
increases both immunosuppressant and potential toxic effects. Thus,
patients on mercaptopurine should be warned about potentially serious
interactions with medications used to treat gout or hyperuricemia,
and the dose should be decreased to 25% of the standard
dose in subjects who are already taking allopurinol.
Methotrexate
Methotrexate was engineered to inhibit dihydrofolate
reductase, thereby blocking DNA synthesis and causing
cell death. First used in cancer treatment, methotrexate
subsequently was recognized to have beneficial effects
in autoimmune diseases such as rheumatoid arthritis
and psoriasis (Chapter 62 discusses the use of
methotrexate in dermatological disorders). The antiinflammatory
effects of methotrexate may involve
mechanisms in addition to inhibition of dihydrofolate
reductase.
As with azathioprine–mercaptopurine, methotrexate generally
is reserved for patients whose IBD is either steroid-resistant or
steroid-dependent. In Crohn’s disease, it both induces and maintains
remission, generally with a more rapid response than that seen with
mercaptopurine or azathioprine (Feagan et al., 1995). Its use in ulcerative
colitis has not been thoroughly investigated.
Therapy of IBD with methotrexate differs somewhat from its
use in other autoimmune diseases. Most important, higher doses
(e.g., 15-25 mg/week) are given parenterally. The increased efficacy
with parenteral administration may reflect the unpredictable intestinal
absorption at higher doses of methotrexate. For unknown reasons,
the incidence of methotrexate- induced hepatic fibrosis in
patients with IBD is lower than that seen in patients with psoriasis.
Use of methotrexate for treatment of IBD has largely been supplanted
by biological therapies (such as anti- TNF α antibodies).
Cyclosporine
The calcineurin inhibitor cyclosporine is a potent
immunomodulator used most frequently after organ
transplantation (Chapter 35). It is effective in specific
clinical settings in IBD, but the high frequency of significant
adverse effects limits its use as a first- line medication.
Cyclosporine is effective in patients with severe ulcerative
colitis who have failed to respond adequately to glucocorticoid
therapy. Between 50% and 80% of these severely ill patients