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

1012 gout, increased P-glycoprotein activity, and hypercholesterolemia.
Nephrotoxicity occurs in the majority of patients and is the major
reason for cessation or modification of therapy (Nankivell et al.,
2003). Recent reviews of calcineurin inhibitor nephrotoxicity are
available (Burdmann et al., 2003). Combined use of calcineurin
inhibitors and glucocorticoids is particularly diabetogenic, although
this apparently is more problematic in patients treated with
tacrolimus (see “Tacrolimus” section earlier). Especially at risk are
obese patients, African-American or Hispanic transplant recipients,
or those with a family history of type II diabetes or obesity.
Cyclosporine, as opposed to tacrolimus, is more likely to produce
elevations in LDL cholesterol (Artz et al., 2003).
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Drug Interactions. Cyclosporine interacts with a wide variety of commonly
used drugs, and close attention must be paid to drug interactions.
Any drug that affects microsomal enzymes, especially
CYP3A, may impact cyclosporine blood concentrations.
Substances that inhibit this enzyme can decrease cyclosporine
metabolism and increase blood concentrations. These include Ca 2+
channel blockers (e.g., verapamil, nicardipine), antifungal agents (e.g.,
fluconazole, ketoconazole), antibiotics (e.g., erythromycin), glucocorticoids
(e.g., methylprednisolone), HIV-protease inhibitors (e.g., indinavir),
and other drugs (e.g., allopurinol, metoclopramide). Grapefruit
juice inhibits CYP3A and the P-glycoprotein multidrug efflux pump
and should be minimized by patients taking cyclosporine because
these effects can increase cyclosporine blood concentrations. In
contrast, drugs that induce CYP3A activity can increase cyclosporine
metabolism and decrease blood concentrations. Such drugs include
antibiotics (e.g., nafcillin, rifampin), anticonvulsants (e.g., phenobarbital,
phenytoin), and others (e.g., octreotide, ticlopidine). In general,
close monitoring of cyclosporine blood levels and the levels of other
drugs is required when such combinations are used.
Interactions between cyclosporine and sirolimus (also see
“Drug Interactions” in the sirolimus section) have led to the recommendation
that administration of the two drugs be separated by time.
Sirolimus aggravates cyclosporine-induced renal dysfunction, while
cyclosporine increases sirolimus-induced hyperlipidemia and myelosuppression.
Other drug interactions of concern include additive
nephrotoxicity when cyclosporine is co-administered with nonsteroidal
anti-inflammatory drugs (NSAIDs) and other drugs that
cause renal dysfunction; elevation of methotrexate levels when the
two drugs are co-administered; and reduced clearance of other drugs,
including prednisolone, digoxin, and statins.
ISATX247. This is a new oral semisynthetic structural analog of
cyclosporine. The cyclosporine molecule is modified at the first amino
acid residue. It is more potent on a weight basis than cyclosporine in
vitro for calcineurin inhibition. Some preclinical studies show reduced
nephrotoxicity, and thus the drug is in clinical development as a
primary immunosuppressive drug. Phase 2 clinical trials are in process
and thus far show similar or less nephrotoxicity with less frequent
glucose intolerance compared to tacrolimus-treated patients (Vincenti
and Kirk, 2008).
Janus Kinase Inhibitors/CP-690550. Cytokine receptors are enticing
targets for modulation by new small immunosuppressive molecules.
Janus kinase (JAK) inhibitors are a class of drugs that inhibit important
cytoplasmic tyrosine kinases that are involved in cell signaling.
The molecule CP-690550 currently is in clinical trials. As an
immunosuppressive drug, this compound inhibits JAK3, which is
found primarily on hematopoietic cells. In preclinical studies, this
JAK3 inhibitor has been tolerated without nephrotoxicity, malignancy,
or other important side effects. To date, all studies have shown
non-inferiority with other standard immunosuppressive regimens
(Vincenti and Kirk, 2008).
Protein Kinase C Inhibitors/AEB071. Various isoforms of PKC are
important mediators in signaling pathways distal to the T-cell receptor
and co-stimulators. AEB071 is a low-molecular-weight compound
that blocks T-cell activation by inhibition of PKC, thus
producing immunosuppression by a different mechanism than calcineurin
inhibitors. Clinical studies are ongoing. Early trials using
PKC inhibitors in combination with calcineurin inhibitors (CNIs)
followed by discontinuation of the CNI had to be stopped because
acute rejections occurred when the CNIs were discontinued
(Vincenti and Kirk, 2008).
Anti-Proliferative and
Antimetabolic Drugs
Sirolimus
Sirolimus (rapamycin; RAPAMUNE) is a macrocyclic lactone
(Figure 35–1) produced by Streptomyces hygroscopicus.
Mechanism of Action. Sirolimus inhibits T-lymphocyte activation and
proliferation downstream of the IL-2 and other T-cell growth factor
receptors (Figure 35–2). Like cyclosporine and tacrolimus, therapeutic
action of sirolimus requires formation of a complex with an
immunophilin, in this case FKBP-12. However, the sirolimus–
FKBP-12 complex does not affect calcineurin activity. It binds to and
inhibits a protein kinase, designated mTOR, which is a key enzyme
in cell-cycle progression. Inhibition of mTOR blocks cell-cycle progression
at the G 1
→ S phase transition. In animal models, sirolimus
not only inhibits transplant rejection, graft-versus-host disease, and a
variety of auto-immune diseases, but its effect also lasts several
months after discontinuing therapy, suggesting a tolerizing effect (see
“Tolerance”) (Groth et al., 1999). A newer indication for sirolimus is
the avoidance of calcineurin inhibitors, even when patients are stable,
to protect kidney function (Flechner et al., 2008).
Disposition and Pharmacokinetics. After oral administration,
sirolimus is absorbed rapidly and reaches a peak blood concentration
within ~1 hour after a single dose in healthy subjects and within ~2
hours after multiple oral doses in renal transplant patients. Systemic
availability is ~15%, and blood concentrations are proportional to
doses between 3 and 12 mg/m 2 . A high-fat meal decreases peak
blood concentration by 34%; sirolimus therefore should be taken
consistently either with or without food, and blood levels should be
monitored closely. About 40% of sirolimus in plasma is protein
bound, especially to albumin. The drug partitions into formed elements
of blood, with a blood-to-plasma ratio of 38 in renal transplant
patients. Sirolimus is extensively metabolized by CYP3A4 and
is transported by P-glycoprotein. Seven major metabolites have been
identified in whole blood. Metabolites also are detectable in feces
and urine, with the bulk of total excretion being in feces. Although
some of its metabolites are active, sirolimus itself is the major active