Cyclosporin in the blood

The concentration of cyclosporin in the blood when used in therapeutic doses (peak concentration) is 150-400 mg / ml. Toxic concentration is more than 400 mg / ml.

The half-life of cyclosporine is 6-15 hours.

Cyclosporine is widely used as an effective immunosuppressant for suppressing the "graft versus host" reaction after bone marrow transplantation, kidney, liver, heart and some autoimmune diseases.

Ciclosporin is a fat-soluble peptide antibiotic that disrupts the early differentiation of T-lymphocytes and blocks their activation. It suppresses the transcription of genes encoding the synthesis of IL-2, 3, γ-interferon and other cytokines produced by antigen-stimulated T lymphocytes, but does not block the influence of other lymphokines on T-lymphocytes and their interaction with antigens.

The drug is administered intravenously and taken orally. When organ transplantation treatment begins 4 to 12 hours before the transplant operation. When transplanting red bone marrow, the initial dose of cyclosporine is administered on the eve of the operation.

Usually the initial dose of the drug is administered intravenously slowly (dropwise for 2-24 hours) in a 0.9% solution of sodium chloride or 5% glucose solution from the calculation of 3-5 mg / (kg.sut). Subsequently, intravenous injections continue for 2 weeks, and then switch to oral maintenance therapy at a dose of 7.5-25 mg / kg daily.

After oral administration, cyclosporine is slowly and not completely absorbed (20-50%). In the blood, 20% of cyclosporine binds to leukocytes, 40% - with red blood cells and 40% is in plasma by HDL. In connection with this distribution of cyclosporine, the determination of its concentration in the blood is preferable to that in plasma or serum, since it more truly reflects the true concentration. Cyclosporine is almost completely metabolized in the liver and is excreted in the bile. The half-life of the drug is 6-15 hours. Anticonvulsants increase the metabolism of cyclosporine, and erythromycin, ketoconazole and calcium channel blockers - reduce. Peak concentrations of cyclosporine for oral administration are noted after 1-8 hours (on average after 3.5 hours), the concentration decreases after 12-18 hours. With intravenous administration, the peak of the cyclosporin concentration in the blood occurs 15-30 minutes after the end of the injection, the decrease occurs after 12 hours.

The main principle of the optimal use of cyclosporine is a balanced choice between the individual therapeutic and toxic concentrations of the drug in the blood. Since cyclosporine has a pronounced intra- and interindividual variability in pharmacokinetics and metabolism, it is very difficult to select an individual dose of the drug. In addition, the dose of cyclosporine taken is poorly correlated with its concentration in the blood. In order to achieve the optimal therapeutic concentration of cyclosporine in the blood, it is necessary to monitor it.

Rules of blood sampling for research. Investigate whole venous blood. Blood is taken into a tube with ethylenediaminetetraacetic acid 12 hours after the administration or administration of cyclosporine. When the kidney is transplanted, the therapeutic concentration of cyclosporine 12 hours after admission should be in the range of 100-200 mg / ml, with a heart transplant - 150-250 mg / ml, the liver - 100-400 mg / ml, red bone marrow - 100-300 mg / ml. Concentration below 100 mg / ml does not have an immunosuppressive effect. However, in the first weeks after transplantation the concentration of cyclosporine below 170 mg / ml can be rejected by the transplant, so it is necessary to maintain it at 200 mg / ml or higher, after 3 months, the concentration is usually reduced to 50-75 ng / ml and maintained at such level for the rest of the patient's life. Periodicity of monitoring of cyclosporine in the blood: daily with liver transplantation and 3 times a week for kidney and heart transplantation.

The most common side effect of cyclosporine is nephrotoxicity, which occurs in 50-70% of patients with kidney transplantation and in a third of patients with heart and liver transplantation. Cyclosporine nephrotoxicity can be manifested by the following syndromes:

• the belated start of the functioning of the transplanted organ, which occurs in 10% of patients not receiving cyclosporine, and in 35% of those receiving it; this problem can be resolved by lowering the dose of cyclosporine;
• reversible decrease in GFR (may occur with a concentration of cyclosporine in the blood of 200 mg / ml or more, and always develops at a concentration exceeding 400 mg / ml); the serum creatinine concentration begins to rise on the 3rd-7th day after an increase in the concentration of cyclosporine, often against oliguria, hyperkalemia and decreased renal blood flow, and decreases 2-14 days after a decrease in the dosage of cyclosporine;
• hemolytic-uremic syndrome;
• chronic nephropathy with interstitial fibrosis, which causes an irreversible loss of renal function.

Usually, these toxic effects are reversible with a decrease in the dosage of the drug, but in most cases it is very difficult to differentiate the cyclosporin nephrotoxicity from the transplant rejection reaction.

Another severe, although less common, side effect of cyclosporine is hepatotoxicity. Liver damage develops in 4-7% of patients with grafts and is characterized by increased activity of ALT, AST, alkaline phosphatase and the concentration of total bilirubin in the blood serum. Manifestations of hepatotoxicity depend on the dose of cyclosporine and are reversible with reduced dosage.

Among other side effects of cyclosporine, arterial hypertension and hypomagnesemia are noted.

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