Analytical Methodologies for Cyclosporine Pharmacokinetics: A Comparison of Radioimmunoassay with High Performance Liquid Chromatography

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Abstract
Radioimmunoassay (RIA) and high performance liquid chromatography (HPLC) with ultraviolet absorbance detection have been compared as potential analytical methods for cyclosporine pharmacokinetic studies. Cyclosporine concentrations were measured by each method in the serum and bile of cyclosporine—treated humans and in the plasma and urine of cyclosporine—treated dogs. While clearly affording greater assay sensitivity, RIA overestimates concentrations of parent cyclosporine, ostensibly because of cross—reactivity with cyclosporine metabolites. Thus, RIA—measured time course data result in underestimations of primary pharmacokinetic parameters, volume of distribution and clearance. Ratios of measured concentrations (RIA/HPLC) in human bile are significantly greater than those in serum, lending further evidence to the previously—suggested metabolite interference with RIA. Similar results were obtained from the urine of cyclosporine—treated dogs. Moreover, ratios (RIA/HPLC) in dog plasma rise and then decline as a function of post—administration time, reaching a peak in approximately 8 hours. This might be consistent with the formation and disposition of metabolites. HPLC appears to be specific for parent cyclosporine. Thus, HPLC—measured time—course data afford more reliable estimates of cyclosporine pharmacokinetic parameters, although for certain studies, sensitivity might be less than adequate.

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