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

1010
TCR
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
IL-2
Receptor
DG 2
X-PO 4
PO 4
X
PLC 1 PO 4
PKC IP 3
Protein Tyrosine
Kinases (Src, Ick,
fyn, Zap 70)
Sirolimus
Ras
Vav or
GRB2/sos
[Ca 2+ ]
FKBP mTOR Cdk 2 IL-2
Protein
Raf-1
Cyclophilin
or FKBP
Calcineurin
Proliferation
MEK
Cyclosporine
or Tacrolimus
P i
MAP Kinase
NFAT c
NFAT c
IL-2 mRNA
Immediate
early genes
fos/jun NFAT n NFAT c
PIP
IL 2 Gene
Figure 35–2. Mechanisms of action of cyclosporine, tacrolimus, and sirolimus on T lymphocytes. Both cyclosporine and tacrolimus bind
to immunophilins (cyclophilin and FK506-binding protein [FKBP], respectively), forming a complex that binds the phosphatase calcineurin
and inhibits the calcineurin-catalyzed dephosphorylation essential to permit movement of the nuclear factor of activated
T cells (NFAT) into the nucleus. NFAT is required for transcription of interleukin-2 (IL-2) and other growth- and differentiationassociated
cytokines (lymphokines). Sirolimus (rapamycin) works at a later stage in T-cell activation, downstream of the IL-2 receptor.
Sirolimus also binds FKBP, but the FKBP-sirolimus complex binds to and inhibits the mammalian target of rapamycin (mTOR),
a kinase involved in cell-cycle progression (proliferation). TCR, T-cell receptor. (From Pattison et al., 1997, with permission. Copyright
© Lippincott Williams & Wilkins. http://lww.com.)
mechanisms such as those underlying transplant rejection and some
forms of auto-immunity. It preferentially inhibits antigen-triggered
signal transduction in T lymphocytes, blunting expression of many
lymphokines, including IL-2, and the expression of anti-apoptotic
proteins. Cyclosporine forms a complex with cyclophilin, a
cytoplasmic-receptor protein present in target cells (Figure 35-2).
This complex binds to calcineurin, inhibiting Ca 2+ -stimulated
dephosphorylation of the cytosolic component of NFAT (Schreiber
and Crabtree, 1992). When cytoplasmic NFAT is dephosphorylated,
it translocates to the nucleus and complexes with nuclear components
required for complete T-cell activation, including transactivation
of IL-2 and other lymphokine genes. Calcineurin phosphatase
activity is inhibited after physical interaction with the
cyclosporine/cyclophilin complex. This prevents NFAT dephosphorylation
such that NFAT does not enter the nucleus, gene transcription
is not activated, and the T lymphocyte fails to respond to specific
antigenic stimulation. Cyclosporine also increases expression of
transforming growth factor β (TGF-β), a potent inhibitor of IL-
2–stimulated T-cell proliferation and generation of cytotoxic T lymphocytes
(CTLs) (Khanna et al., 1994).
Disposition and Pharmacokinetics. Cyclosporine can be administered
intravenously or orally. The intravenous preparation (SANDIMMUNE,
others) is provided as a solution in an ethanol-polyoxyethylated castor
oil vehicle that must be further diluted in 0.9% sodium chloride
solution or 5% dextrose solution before injection. The oral dosage
forms include soft gelatin capsules and oral solutions. Cyclosporine
supplied in the original soft gelatin capsule is absorbed slowly, with
20-50% bioavailability. A modified microemulsion formulation
(NEORAL) has become the most widely used preparation. It has more
uniform and slightly increased bioavailability compared to the original
formulation. It is provided as 25-mg and 100-mg soft gelatin