Monitoring Free Concentrations of Immunosuppressant Drugs

Immunosuppressants such as cyclosporine, tacrolimus, and mycophenolic acid mofetil are strongly bound to serum proteins. Cyclosporine is strongly bound in plasma mainly to lipoproteins, and the unbound fraction is usually 2%. Some evidence also indicates that the unbound concentration of cyclosporine has a closer association with both kidney and heart allograft rejection than total concentrations. However, measuring free cyclosporine concentration is inherently complex and not usually performed in clinical laboratories (15). Mendonza et al. described a liquid chromatography—tandem mass spectrometric technique for determination of cyclosporine concentrations in saliva. For a highly protein-bound drug such as cyclosporine, saliva offered a simple way to determine free cyclosporine concentration (16).

Another widely used immunosuppressant drug, tacrolimus, is also strongly bound to erythrocytes and serum proteins. Warty et al. (17) studied the distribution of tacrolimus in 13 transplant recipients and reported that in plasma 64 ± 8% of tacrolimus was associated with lipoprotein-deficient plasma 21.0 ± 8% associated with high-density lipoprotein, 3.0 ± 3% associated with low-density lipoprotein, and 11.0 ± 3% associated with very low-density lipoprotein. Piekoszewski et al. (18) reported that the plasma protein binding of tacrolimus was on average 72%. Zahir et al. reported that unbound concentrations of tacrolimus were significantly lower during episodes of rejection, and in patients experiencing tacrolimus-related side effects, only the unbound concentrations of tacrolimus were found to be significantly higher. Blood distribution and protein binding of tacrolimus also change significantly in the posttransplant period, leading to changes in unbound tacrolimus concentrations (19). Another study also confirmed that unbound concentrations of tacrolimus were lower in liver transplant recipients experiencing rejection (20).

Mycophenolate mofetil is a prodrug which is converted into mycophenolic acid. The plasma protein binding increases with time after liver transplant from 92 to 98% causing intraindividual variation in liver transplant recipients (21). Atcheson et al. reported that mycophenolic acid Fu varied 11-fold from 1.6 to 18.3% whereas the metabolite glucuronide fraction varied threefold from 17.4 to 54.1%. There were positive correlations between urea and creatinine concentrations and free mycophenolic acid concentrations, whereas there was a negative correlation between albumin concentration and free mycophenolic acid concentration. The authors further reported that on average free mycophenolic acid Fu was 70% higher in patients with albumin concentrations below 3.1gm/dL than in patients with normal albumin concentrations. Patients with marked renal impairment showed higher free concentrations of mycophenolic acid. The exposure to unbound mycophenolic acid was significantly related to infections and hematological toxicity but neither free nor total mycophenolic acid concentration was related to rejection episodes (22). High-unbound mycophenolic acid concentration was also encountered in a hematopoietic cell transplant patient with sepsis, renal, and hepatic dysfunction (23). Concentrations of free mycophenolic acid can be measured in protein-free ultrafiltrate after solid phase extraction using SPE C-18 cartridges and liquid chromatography combined with tandem mass spectrometry (24).

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