Cipol-N Mechanism of Action

Pharmacology: Pharmacodynamics: Cyclosporine (cyclosporine A) is a cyclosporine immunosuppressive agent. The drug is a nonpolar, cyclic polypeptide antibiotic consisting of 11 amino acids. In vivo studies in animals have shown that cyclosporine inhibits cell-mediated immune responses such as allograft rejection, delayed hypersensitivity (e.g., tuberculin-induced), experimental allergic encephalomyelitis, Freund's adjuvant-induced arthritis, and graft-vs-host disease.
Cyclosporine has also been shown to inhibit primary and secondary responses to T cell-dependent antigens. Increased survival of allogeneic (homologous) transplants involving skin, heart, kidney, liver, pancreas, bone marrow, small intestine, and lung has been shown in animals receiving the drug.
It has been suggested that the immunosuppressive action of cyclosporine results from specific and reversible inhibition of immunocompetent T cells (T-lymphocytes) in the G₀ or G₁ phase of the cell cycle. Cyclosporine inhibits production and/or release of lymphokines including interleukin-2 (T-cell growth factor) and interleukin-1 (lymphocyte-activating factor).
Cyclosporine inhibits the release of interleukin-2 from activated T cells and also inhibits interleukin-2-induced activation of resting T cells; the drug does not appear to inhibit activation of resting T cells that is induced by exogenous interleukin-2. Cyclosporine does not affect the function of phagocytic cells or that of tumor cells. In one study following administration of high dosages of cyclosporine, bone marrow cell counts showed only slight reductions in cell numbers; proliferation of bone marrow stem cells was normal or enhanced.
Pharmacokinetics: Absorption: Following oral administration, cyclosporine is variably and incompletely absorbed. The extent of absorption depends on the individual patient, patient population (e.g., transplant type), post-transplantation time (e.g. increasing during the early post-transplantation period in renal transplant recipients), bile flow (micellar absorption of the drug involving bile), GI state (e.g., decreased with diarrhea), and the formulation administered. Although the absolute oral bioavailability of cyclosporine administered as the modified oral formulations has not been determined in adults, these formulations have greater bioavailability than the conventional oral formulations of cyclosporine. The higher bioavailability of the modified oral formulations relative to the conventional oral formulation varies across patient populations. Food decreases the AUC and peak blood concentration of cyclosporine attained with the modified oral formulations.
Distribution: Cyclosporine is widely distributed into body fluids and tissues, with most of the drug being distributed outside the blood volume. Approximately 90-98% of cyclosporine in plasma is protein bound, mainly to lipoproteins (85-90% of total protein binding). Of lipoprotein binding, 43-57% is to high density lipoproteins (HDLs), 25% to low density lipoproteins (LDLs), and 2% to very-low-density lipoproteins (VLDLs). Distribution of the drug in blood is dose dependent; in vitro in blood, 33-47% of the drug is distributed into plasma, 4-9% into lymphocytes, 4-12% into granulocytes, and 41-58% into erythrocytes. At high concentrations, distribution of cyclosporine into leukocytes and erythrocytes becomes saturated. Concentrations of the drug achieved in mononuclear cells have been reported to be 1000 times greater than those achieved in erythrocytes. Cyclosporine crosses the placenta in animals and humans and is distributed into milk.
Metabolism: Cyclosporine is extensively metabolized in the liver via the cytochrome P-450 enzyme system, principally by the CYP3A isoenzyme, and less extensively in the GI tract and the kidney to at least 30 metabolites found in bile, feces, blood and urine. The drug undergoes extensive first-pass metabolism following oral administration. Several major metabolic pathways, including hydroxylation of the Cγ-carbon of 2 leucine residues, Cλ-carbon hydroxylation and cyclic ether formation (with oxidation of the double bond) in the side chain of the amino acid 3-hydroxyl-N,4-dimethyl-1-2 amino-6-octenoic acid, and N-demethylation of N-methyl leucine residues, are involved. Conjugation of these metabolites or hydrolysis of the cyclic peptide chain does not appear to be an important pathway for cyclosporine metabolism. Oxidation of cyclosporine at its 1-λ, 4-N-desmethylated, and 9-γ positions yields the major metabolites known as AM1 (M17), AM4N (M21), AM9 (M1), respectively.
Elimination: Cyclosporine is principally excreted via bile, almost entirely as metabolites. Only about 6% of a dose of the drug is excreted in urine, with 0.1% of a dose being excreted unchanged. However, urinary excretion of unchanged drug may be increased in certain patient populations (e.g., early posttransplant period in bone marrow allograft recipients) and in younger patients. The clearance of cyclosporine reportedly is not changed substantially by renal failure or dialysis.