Cyclosporine plasma unbound fraction in heart and lung transplantation recipients

To investigate the variability in the unbound fraction (f(U)) of cyclospori ne in recipients of heart, heart-lung, and lung transplantation, cyclospori ne f(U) was determined ex vivo in plasma by equilibrium dialysis. In a retr ospective study, 260 samples of plasma tone to seven per patient) were obta ined from 89 heart (86%), lung (9%), and heart-lung (5%) transplant patient s. The unbound fraction (x100) of cyclosporine ranged from 0.52% to 3.94%, with an overall mean of 1.53% +/- 0.375% (SD). The mean percentage unbound for individual patients ranged from 0.71% to 1.98%, giving a 2.8-fold inter patient variation. In heart transplant recipients (66 patients), the values of f(U) were significantly lower (p < 0.01) during more severe rejection e pisodes, which required antirejection treatment (endomycardial biopsy resul t of grade 3a and higher) than in the absence of rejection (grade 0) or dur ing grade la rejections. The value of f(U) did not vary with organ transpla nted (p = 0.35) or etiology of organ failure (p = 0.32). Cyclosporine f(U) was negatively correlated with the age of the patient (r = -0.18, p < 0.05) . Correlations were not observed between f(U) and blood biochemical and cyt ologic indices. However, f(U) was significantly lower (p < 0.01) in hyperch olesterolemic transplant recipients (1.37 +/- 0.52%) than in normocholester olemic patients (1.60 +/- 0.63%). Administration of simvastatin resulted in a significant increase in the mean f(U) from 1.40 +/- 0.09%) to 1.82 +/- 0 .13% (paired t test, n = 13; p < 0.01). In patients who received ketoconazo le, f(U) was not different from controls. These findings suggest that the l evel of cyclosporine f(U) may be an important determinant of immunosuppress ive activity of cyclosporine. Moreover, the variation in f(U) could be stro ngly related to the concentration of serum Lipoproteins; interpretation of the results of cyclosporine monitoring thus requires consideration of the l ipidemic status of the patient.