Cyclosporine in the blood

The concentration of cyclosporine in the blood when used in therapeutic doses (peak concentration) is 150-400 mg/ml. The 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 to suppress the graft-versus-host reaction after bone marrow, kidney, liver, and heart transplants and in the treatment of certain autoimmune diseases.

Cyclosporine is a lipid-soluble peptide antibiotic that disrupts early differentiation of T lymphocytes and blocks their activation. It suppresses 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 effect of other lymphokines on T lymphocytes and their interaction with antigens.

The drug is administered intravenously and taken orally. In organ transplantation, treatment begins 4-12 hours before the transplantation operation. In red bone marrow transplantation, the initial dose of cyclosporine is administered the day before the operation.

Usually the initial dose of the drug is administered intravenously slowly (by drip over 2-24 hours) in 0.9% sodium chloride solution or 5% glucose solution at a rate of 3-5 mg/(kg.day). Subsequently, intravenous injections are continued for 2 weeks, and then switched to oral maintenance therapy at a dose of 7.5-25 mg/kg daily.

After oral administration, cyclosporine is slowly and incompletely absorbed (20-50%). In the blood, 20% of cyclosporine binds to leukocytes, 40% to erythrocytes, and 40% is in the plasma on HDL. Due to this distribution of cyclosporine, determining its concentration in the blood is preferable to that in plasma or serum, since it more accurately reflects the true concentration. Cyclosporine is almost completely metabolized in the liver and excreted in the bile. The half-life of the drug is 6-15 hours. Anticonvulsants increase the metabolism of cyclosporine, while erythromycin, ketoconazole, and calcium channel blockers decrease it. The peak concentration of cyclosporine after oral administration is observed after 1-8 hours (on average - after 3.5 hours), the concentration decreases after 12-18 hours. With intravenous administration, the peak concentration of cyclosporine in the blood occurs 15-30 minutes after the end of administration, the decrease occurs after 12 hours.

The basic principle of optimal use of cyclosporine is a balanced choice between individual therapeutic and toxic concentrations of the drug in the blood. Since cyclosporine has 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 correlates poorly 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 for collecting blood for research. Whole venous blood is tested. Blood is taken into a test tube with ethylenediaminetetraacetic acid 12 hours after taking or administering cyclosporine. In case of kidney transplantation, the therapeutic concentration of cyclosporine 12 hours after taking should be in the range of 100-200 mg/ml, in case of heart transplantation - 150-250 mg/ml, 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, if the cyclosporine concentration is below 170 mg/ml, the transplant may be rejected, so it is necessary to maintain it at a level of 200 mg/ml or higher; after 3 months, the concentration is usually reduced to 50-75 ng/ml and maintained at this level for the rest of the patient's life. The frequency of monitoring cyclosporine in the blood: daily for 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 kidney transplant patients and in one-third of heart and liver transplant patients. Cyclosporine nephrotoxicity may manifest itself in the following syndromes:

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

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

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

Other side effects of cyclosporine include hypertension and hypomagnesemia.

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