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Cyclosporin

Cyclosporin is primarily used to prevent the rejection of transplanted organs. However, it has also been used in a wide range of other conditions, including psoriasis, rheumatoid arthritis, and astham

Monitoring whole blood concentrations of cyclosporin is an important part of treatment since its toxic:therapeutic ratio is very low. Also, the variable pharmacokinetics of cyclosporin among patients make accurate prediction of the initial dosage difficult. This variability results from differences in the drug's absorption, distribution, and clearance.

Cyclosporin is fat soluble and some of the variability in its disposition may result from distribution into body fat. In addition, its apparent volume of distribution may be altered in patients with liver or renal disease.

Another important aspect in its distribution is that it is highly bound to erythrocytes and plasma lipoproteins. At low blood concentrations (below 80 nmol/l (100 ng/ml)) and when the packed cell volume is low (for example, in patients with kidney failure) the contribution of the plasma bound fraction becomes more important to the disposition of the drug. Cyclosporin is metabolised in the liver and its clearance may therefore be reduced in patients with liver disease. Both cyclosporin and its metabolites are excreted in bile and little cyclosporin appears in the urine. Thus renal impairment does not alter the elimination of cyclosporin.

Measurement techniques

cyclosporin

The method of measuring the blood cyclosporin concentration is crucial to its use in monitoring treatment.

Blood cyclosporin concentration is determined by two factors: the element of the blood used for the assay (plasma, serum, or whole blood) and the type of assay.

Type of sample

The distribution of cyclosporin into erythrocytes is temperature dependent. The drug tends to bind to erythrocyte membranes after sampling, particularly if the sample is allowed to cool. For this reason some investigators separate the plasma or serum from whole blood samples at 37C and reheat to 37C samples which have been allowed to cool. Others prefer to separate all plasma and serum samples at 4C. An alternative method is to measure the concentration in whole blood, in which case temperature is irrelevant.

Ethylenediamine tetraacetic acid (EDTA) should be used as an anticoagulant and blood should not be drawn through plastic cannulas through which cyclosporin has previously been given.

Type of assay

Two main assay techniques are available: radioimmunoassay and high performance liquid chromatography.

Early radioimmunoassays used non-specific antibodies, which cross reacted with metabolites of cyclosporin. More recently, however, antibodies (both monoclonal and polyclonal) specific for cyclosporin have been developed, and these may yield more reproducible results. Indeed, the results with these antibodies are similar to those with high performance liquid chromatography, a specific method in which cyclosporin is separated from its metabolites as part of the assay procedure. Because sample preparation and assay technique are more complicated with high performance liquid chromatography it is not as widely used as radioimmunoassay.

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