Diurnal variation in cyclosporine kinetics.

Cyclosporine (Cy A) is now considered a primary immunosuppressant used to prevent organ rejection in liver, kidney, and heart transplant patients (1-3). It has been recommended that the blood level of Cy A be monitored in these patients to minimize the possibility of rejection due to low CyA blood concentrations or potential toxicity due to high CyA concentrations (4,5). This is based on the observation of marked variations in the trough Cy A blood levels between and within patients. Such variations in blood levels are the result of pronounced differences in the pharmacokinetic parameters, such as clearance and bioavailability (6-8). We report on one factor, diurnal variation, that may contribute to the observed variability in the pharmacokinetics of Cy A in transplant patients. Cy A pharmacokinetics were studied during two or three different dosing intervals (8 h) in two patients who underwent orthotopic liver transplantation at the University of Pittsburgh. The same maintenance dose of CyA (patient 1, 140 mg; patient 2, 150 mg) was administered over 1 h as an intravenous infusion in the morning and at night. Hourly blood samples were drawn and analyzed for cycIosporine following modifications of a high pressure liquid chromatographic assay (9). Kinetic parameters were calculated according to standard techniques (10). The biochemical profiles on different study periods in a given patient were similar.