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

1014 common), and/or anemia (uncommon). Other important adverse
effects include increased susceptibility to infections (especially varicella
and herpes simplex viruses), hepatotoxicity, alopecia, GI toxicity,
pancreatitis, and increased risk of neoplasia.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Drug Interactions. Xanthine oxidase, an enzyme of major importance
in the catabolism of azathioprine metabolites, is blocked by allopurinol.
If azathioprine and allopurinol are used concurrently, the azathioprine
dose must be decreased to 25-33% of the usual dose; it is
best not to use these two drugs together. Adverse effects resulting
from co-administration of azathioprine with other myelosuppressive
agents or angiotensin-converting enzyme inhibitors include leukopenia,
thrombocytopenia, and anemia as a result of myelosuppression.
Mycophenolate Mofetil
Mycophenolate mofetil (MMF; CELL-CEPT) is the
2-morpholinoethyl ester of mycophenolic acid (MPA).
Mechanism of Action. MMF is a prodrug that is rapidly hydrolyzed to
the active drug, MPA, a selective, noncompetitive, reversible inhibitor
of inosine monophosphate dehydrogenase (IMPDH), an important
enzyme in the de novo pathway of guanine nucleotide synthesis. B
and T lymphocytes are highly dependent on this pathway for cell proliferation,
while other cell types can use salvage pathways; MPA
therefore selectively inhibits lymphocyte proliferation and functions,
including antibody formation, cellular adhesion, and migration.
Disposition and Pharmacokinetics. MMF undergoes rapid and complete
metabolism to MPA after oral or intravenous administration.
MPA, in turn, is metabolized to the inactive phenolic glucuronide
MPAG. The parent drug is cleared from the blood within a few minutes.
The t 1/2
of MPA is ~16 hours. Negligible (<1%) amounts of
MPA are excreted in the urine. Most (87%) is excreted in the urine
as MPAG. Plasma concentrations of MPA and MPAG are increased
in patients with renal insufficiency. In early renal transplant patients
(<40 days after transplant), plasma concentrations of MPA after a
single dose of MMF are about half of those found in healthy volunteers
or stable renal transplant patients.
Therapeutic Uses. MMF is indicated for prophylaxis of
transplant rejection, and it typically is used in combination
with glucocorticoids and a calcineurin inhibitor but
not with azathioprine. Combined treatment with
sirolimus is possible, although potential drug interactions
necessitate careful monitoring of drug levels.
For renal transplants, 1 g is administered orally or intravenously
(over 2 hours) twice daily (2 g/day). A higher dose, 1.5 g
twice daily (3 g/day), may be recommended for African-American
renal transplant patients and all liver and cardiac transplant patients.
MMF is increasingly used off label in systemic lupus.
Toxicity. The principal toxicities of MMF are gastrointestinal and
hematologic. These include leukopenia, pure red cell aplasia, diarrhea,
and vomiting. There also is an increased incidence of some infections,
especially sepsis associated with cytomegalovirus; progressive multifocal
leukoencephalopathy also has been reported in conjunction with
the administration of MMF. Tacrolimus in combination with MMF
has been associated with activation of polyoma viruses such as BK
virus, which can cause interstitial nephritis difficult to distinguish from
acute rejection (Hirsch et al., 2002). Excessive immunosuppression is
suspected to be responsible for this adverse effect, not necessarily this
widely used drug combination. The use of mycophenolate in pregnancy
is associated with congenital anomalies and increased risk of
pregnancy loss. Women of childbearing potential taking mycophenolate
must use effective contraception.
Drug Interactions. Potential drug interactions between MMF and
several other drugs commonly used by transplant patients have
been studied. There appear to be no untoward effects produced
by combination therapy with cyclosporine, trimethoprim–
sulfamethoxazole, or oral contraceptives. Unlike cyclosporine,
tacrolimus delays elimination of MMF by impairing the conversion
of MPA to MPAG. This may enhance GI toxicity. Co-administration
with antacids containing aluminum or magnesium
hydroxide leads to decreased absorption of MMF; thus, these drugs
should not be administered simultaneously. MMF should not be
administered with cholestyramine or other drugs that affect enterohepatic
circulation. Such agents decrease plasma MPA concentrations,
probably by binding free MPA in the intestines. Acyclovir
and ganciclovir may compete with MPAG for tubular secretion,
possibly resulting in increased concentrations of both MPAG and
the antiviral agents in the blood, an effect that may be compounded
in patients with renal insufficiency.
A delayed-release tablet form of MPA (MYFOR-
TIC) also is available. It does not release MPA under
acidic conditions (pH <5) such as in the stomach but is
highly soluble in neutral pH present in the intestine. The
enteric coating results in a delay in the time to reach
maximum MPA concentrations and may improve GI
tolerability, although data are sparse and not convincing
(Darji et al., 2008).
Other Anti-Proliferative and Cytotoxic Agents. Many of
the cytotoxic and antimetabolic agents used in cancer
chemotherapy (Chapter 61) are immunosuppressive due
to their action on lymphocytes and other cells of the
immune system. Other cytotoxic drugs that have been
used off label as immunosuppressive agents include
methotrexate, cyclophosphamide, thalidomide (THALO-
MID), and chlorambucil (LEUKERAN). Methotrexate is used
for treatment of graft-versus-host disease, rheumatoid
arthritis, psoriasis, and some cancers. Cyclophosphamide
and chlorambucil are used in leukemia and lymphomas
and a variety of other malignancies. Cyclophosphamide
also is FDA approved for childhood nephrotic syndrome
and is used widely for treatment of severe systemic lupus
erythematosus and other vasculitides such as Wegener’s
granulomatosis. Leflunomide (ARAVA, others) is a pyrimidine-synthesis
inhibitor indicated for the treatment of
adults with rheumatoid arthritis (Prakash and Jarvis,
1999). This drug has found increasing empirical use in