Cyclosporine plasma unbound fraction in heart and lung transplantation recipients

To investigate the variability in the unbound fraction (f(U)) of cyclosporine in recipients of heart, heart-lung, and lung transplantation, cyclosporine f(U) was determined ex vivo in plasma by equilibrium dialysis. In a retrospective study, 260 samples of plasma tone to seven per patient) were obtained from 89 heart (86%), lung (9%), and heart-lung (5%) transplant patients. 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 interpatient variation. In heart transplant recipients (66 patients), the values of f(U) were significantly lower (p < 0.01) during more severe rejection episodes, which required antirejection treatment (endomycardial biopsy result of grade 3a and higher) than in the absence of rejection (grade 0) or during grade la rejections. The value of f(U) did not vary with organ transplanted (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 cytologic indices. However, f(U) was significantly lower (p < 0.01) in hypercholesterolemic transplant recipients (1.37 +/- 0.52%) than in normocholesterolemic 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 ketoconazole, f(U) was not different from controls. These findings suggest that the level of cyclosporine f(U) may be an important determinant of immunosuppressive activity of cyclosporine. Moreover, the variation in f(U) could be strongly related to the concentration of serum Lipoproteins; interpretation of the results of cyclosporine monitoring thus requires consideration of the lipidemic status of the patient.