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

1008 other immunosuppressive agents to prevent and treat
transplant rejection. High-dose pulses of intravenous
methylprednisolone sodium succinate (SOLU-MEDROL,
others) are used to reverse acute transplant rejection and
acute exacerbations of selected auto-immune disorders.
Glucocorticoids also are efficacious for treatment of
graft-versus-host disease in bone-marrow transplantation.
Glucocorticoids are routinely used to treat autoimmune
disorders such as rheumatoid and other
arthritides, systemic lupus erythematosus, systemic dermatomyositis,
psoriasis and other skin conditions,
asthma and other allergic disorders, inflammatory
bowel disease, inflammatory ophthalmic diseases,
auto-immune hematological disorders, and acute exacerbations
of MS (see “Multiple Sclerosis”). In addition,
glucocorticoids limit allergic reactions that occur with
other immunosuppressive agents and are used in transplant
recipients to block first-dose cytokine storm
caused by treatment with muromonab-CD3 and to a
lesser extent ATG (see “Antithymocyte Globulin”).
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Toxicity. Unfortunately, the extensive use of steroids often results in
disabling and life-threatening adverse effects. These effects include
growth retardation in children, avascular necrosis of bone, osteopenia,
increased risk of infection, poor wound healing, cataracts, hyperglycemia,
and hypertension (Chapter 42). The advent of combined
glucocorticoid/calcineurin inhibitor regimens has allowed reduced
doses or rapid withdrawal of steroids, resulting in lower steroidinduced
morbidities.
Calcineurin Inhibitors
Perhaps the most effective immunosuppressive drugs
in routine use are the calcineurin inhibitors, cyclo -
sporine and tacrolimus, which target intracellular
signaling pathways induced as a consequence of
T cell–receptor activation. Although they are structurally
unrelated (Figure 35-1) and bind to distinct
(albeit related) molecular targets, they inhibit normal
T-cell signal transduction essentially by the same mechanism
(Figure 35–2). Cyclosporine and tacrolimus do
not act per se as immunosuppressive agents. Instead,
these drugs bind to an immunophilin (cyclophilin for
cyclosporine [see “Cyclosporine”] or FKBP-12 for
tacrolimus [see “Tacrolimus”]), resulting in subsequent
interaction with calcineurin to block its phosphatase
activity. Calcineurin-catalyzed dephosphorylation is
required for movement of a component of the nuclear
factor of activated T lymphocytes (NFAT) into the
nucleus (Figure 35–2). NFAT, in turn, is required to
induce a number of cytokine genes, including that for
interleukin-2 (IL-2), a prototypic T-cell growth and differentiation
factor.
Tacrolimus. Tacrolimus (PROGRAF, FK506) is a macrolide
antibiotic produced by Streptomyces tsukubaensis (Goto
et al., 1987). Because of perceived slightly greater efficacy
and ease of blood level monitoring, tacrolimus has
become the preferred calcineurin inhibitor in most transplant
centers (Ekberg et al., 2008).
Mechanism of Action. Like cyclosporine, tacrolimus inhibits T-cell
activation by inhibiting calcineurin. Tacrolimus binds to an intracellular
protein, FK506-binding protein–12 (FKBP-12), an
immunophilin structurally related to cyclophilin. A complex of
tacrolimus-FKBP-12, Ca 2+ , calmodulin, and calcineurin then forms,
and calcineurin phosphatase activity is inhibited. As described for
cyclosporine and depicted in Figure 35–2, the inhibition of phosphatase
activity prevents dephosphorylation and nuclear translocation
of NFAT and inhibits T-cell activation. Thus, although the
intracellular receptors differ, cyclosporine and tacrolimus target the
same pathway for immunosuppression.
Disposition and Pharmacokinetics. Tacrolimus is available for oral
administration as capsules (0.5, 1, and 5 mg) and as a solution for
injection (5 mg/mL). Immunosuppressive activity resides primarily in
the parent drug. Because of intersubject variability in pharmacokinetics,
individualized dosing is required for optimal therapy. Whole
blood, rather than plasma, is the most appropriate sampling compartment
to describe tacrolimus pharmacokinetics. For tacrolimus, the
trough drug level seems to correlate better with clinical events than it
does for cyclosporine. Target concentrations in most centers are
10-15 ng/mL in the early preoperative period and 100-200 ng/mL
3 months after transplantation. Gastrointestinal absorption is incomplete
and variable. Food decreases the rate and extent of absorption.
Plasma protein binding of tacrolimus is 75-99%, involving primarily
albumin and α 1
-acid glycoprotein. The t 1/2
of tacrolimus is ~12 hours.
Tacrolimus is extensively metabolized in the liver by CYP3A; at least
some of the metabolites are active. The bulk of excretion of the parent
drug and metabolites is in the feces. Less than 1% of administered
tacrolimus is excreted unchanged in the urine.
Therapeutic Uses. Tacrolimus is indicated for the prophylaxis
of solid-organ allograft rejection in a manner similar
to cyclosporine (see “Cyclosporine”) and is used off
label as rescue therapy in patients with rejection episodes
despite “therapeutic” levels of cyclosporine.
Recommended initial oral doses are 0.2 mg/kg/day for adult
kidney transplant patients, 0.1-0.15 mg/kg/day for adult liver transplant
patients, 0.075 mg/kg/day for adult heart transplant patients,
and 0.15-0.2 mg/kg/day for pediatric liver transplant patients in two
divided doses 12 hours apart. These dosages are intended to achieve
typical blood trough levels in the 5- to 20-ng/mL range.
Toxicity. Nephrotoxicity, neurotoxicity (e.g., tremor, headache, motor
disturbances, seizures), GI complaints, hypertension, hyperkalemia,
hyperglycemia, and diabetes all are associated with tacrolimus use.
As with cyclosporine, nephrotoxicity is limiting. Tacrolimus has a
negative effect on pancreatic islet β cells, and glucose intolerance and
diabetes mellitus are well-recognized complications of tacrolimusbased
immunosuppression. As with other immunosuppressive agents,