Saturable binding of cyclosporin A to erythrocytes: estimation of binding parameters in renal transplant patients and implications for bioavailability assessment.

Cyclosporin (CyA) exhibits saturable binding to erythrocytes. A one-site binding model was fitted to data from renal transplant patients receiving CyA therapy. The average maximum binding capacity is 2560 micrograms CyA/liter of packed erythrocytes; the unbound CyA concentration associated with 50% saturation of the binding site is 67 micrograms/liter. Analysis indicates that whole-blood CyA measurement to monitor drug therapy should be viewed cautiously, particularly when the hematocrit varies considerably. The error in estimating absolute bioavailability at steady state from whole-blood measurements, resulting as a consequence of the saturable binding, has been explored. Although extrapolation to the therapeutic situation, which involves transient drug administration, is difficult, errors of up to 25% are anticipated. When an accurate estimate of bioavailability is required, analysis based on plasma data is proposed. For bioequivalence testing, both blood and plasma CyA data are equally acceptable.