Cyclosporine plasma unbound fraction in heart and lung transplantation recipients.
To investigate the variability in the unbound fraction (fu) of cyclosporine in recipients of heart, heart-lung, and lung transplantation, cyclosporine fu was determined ex vivo in plasma by equilibrium dialysis. In a retrospective study, 260 samples of plasma (one 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 fu 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 fu did not vary with organ transplanted (p = 0.35) or etiology of organ failure (p = 0.32). Cyclosporine fu was negatively correlated with the age of the patient (r = -0.18, p < 0.05). Correlations were not observed between fu and blood biochemical and cytologic indices. However, fu 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 fu from 1.40+/-0.09%) to 1.82+/-0.13% (paired t test, n = 13; p < 0.01). In patients who received ketoconazole, fu was not different from controls. These findings suggest that the level of cyclosporine fu may be an important determinant of immunosuppressive activity of cyclosporine. Moreover, the variation in fu 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.
Department of Pharmacy, University of Sydney, Australia.
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Akhlaghi
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Ashley
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Keogh
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Brown
D000293:Adolescent; D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000097:blood* / Q000627:therapeutic use; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology / Q000517:prevention & control; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000627:therapeutic use; D008055:Lipids / Q000097:blood; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D013997:Time Factors
D007166:Immunosuppressive Agents; D008055:Lipids; D016572:Cyclosporine