Cyclosporine (previously called “cyclosporin A”) is a compound derived from a soil fungus that has strong immunosuppressive activity and is widely used to prevent transplant rejection. Cyclosporine is thought to inhibit helper T-cell function with minimal effect on B-cell function. Cyclosporine can be administered orally or intravenously. If given orally, it is absorbed through the lymphatics of the distal ileum, with considerable variability in time and degree of absorption. During the immediate postabsorptive period, 8%-60% of the dose is absorbed, although later absorption may improve somewhat. After an oral dose, peak serum levels are reached in about 2.5 hours, and subsequent body elimination half-life is about 4 hours. There is wide variation of these two parameters between individual patients (e.g., elimination time variation of 4.3-53 hours in renal transplant patients). About 50%-60% of the absorbed dose is bound to RBCs, 25%-35% is in plasma, and about 10%-15% is bound to leukocytes. The plasma component is about 60% bound to high-density lipoproteins, about 25% to low-density lipoproteins, and about 10% to other plasma proteins, leaving about 5% unbound. Almost all of the drug is metabolized by the liver microsome system into various derivatives that are excreted in bile and feces, with only 1%-6% of the metabolites excreted in urine. There are several serious side effects. About 25% of transplant patients show some degree of renal toxicity. Lesser numbers develop hypertension or liver toxicity.

Cyclosporine assay. The blood concentration of cyclosporine cannot be predicted from an oral dose. In addition, there is a narrow balance between insufficient immunosuppression with too little drug and inducement of toxicity with too much. Therefore, TDM is considered essential. However, there is considerable controversy in the literature regarding the technical details of cyclosporine TDM. Either whole blood or plasma can be analyzed. Distribution of the drug between plasma and RBCs is temperature dependent, with decrease in serum concentration as temperature decreases. Therefore, to obtain plasma, one must equilibrate the blood at a fixed temperature, and this temperature will influence the assay value. On the other hand, whole blood assay results are affected by the patient hematocrit. Whole blood assay is recommended by the AACC Task Force on Cyclosporine Monitoring (1987). The two widely used assay methods are HPLC and RIA. RIA produces higher values than HPLC and includes some cross-reacting metabolites with the cyclosporine measurement. The HPLC assay is more specific since it does not include metabolites. However, there are many published HPLC procedures that vary in one or more technical details. At present, there is no consensus on a single analytic protocol, and since different methods and technical variations produce different results, an exact therapeutic range has not been established. Average values from the literature are 250-1,000 µg/L using whole blood by RIA, 50-200 µg/L using plasma by RIA, and 100-500 µg/L using whole blood by HPLC. Trough levels are usually obtained. Certain medications affect cyclosporine assay, such as phenytoin, which activates the liver microsome system.

FK-506 (tacrolimus). This is a recent bacteria-derived macrolide immunosuppressive agent that selectively suppresses both helper/inducer and cytotoxic T-lymphocyte activity, similar to the action of cyclosporine. It appears to have immunosuppressive activity equal to or greater than cyclosporine (especially in liver transplants) with substantially less toxicity. However, nephrotoxicity may occur. Use of medications inhibiting liver microsomal activity (e.g., cinetidine, erythromycin, ketoconazole) increases FK-506 plasma concentration. Assay for FK-506 is possible using monoclonal antibody enzyme immunoassay methods, although these are “first generation” and need to be improved. The therapeutic range is also not standardized and is probably method dependent.