Comparison of cyclosporine assay methodology in the immediate postoperative period of renal transplantation

The method of measurement of cyclosporine concentrations in renal transplant recipients varies between centers and employs either high-performance liquid chromatography (HPLC) or radioimmunoassay (RIA). The merit of using HPLC for identifying the parent compound versus the RIA technique, which also measures certain cross-reactive metabolites that accumulate during renal impairment, is controversial. As a result of the lack of uniformity among centers, an abundance of complex literature that describes the disposition of this potent immunosuppressive agent, as well as a wide range of guidelines for therapeutic monitoring, has evolved. To examine the influence of assay methodology on the repeated determination of cyclosporine in the immediate postoperative period, a time when renal function is often unstable, eight renal transplant recipients were studied after i.v. and oral administration on up to four separate occasions. Whole-blood samples were analyzed by HPLC and RIA. Intravenous kinetic analysis yielded a mean total body clearance of 0.24 ± 0.2 L/min (RIA) and 0.31 ± 0.1 L/min (HPLC) (p > 0.05), the mean volume of distribution was 2.17 ± 0.6 L/kg (RIA) and 2.75 ± 1.2 L/kg (HPLC) (p > 0.05), and a mean half-life was 11.7 ± 4.4 h (RIA) and 12.8 ± 3.8 h (HPLC) (p > 0.05). The mean bioavailability was 0.36 ± 0.23 (RIA) and 0.28 ± 0.15 (HPLC) (p > 0.05). Regression of the 12-h cyclosporine (RIA versus HPLC) concentration yielded a line described by the following equation: RIA = 72 + 1.6 (HPLC). The mean ratios (RIA/HPLC) of the area under the blood cyclosporine concentration versus the time curve (AUC) were 1.6,1.5, and 1.7 during the oral study periods and were poorly correlated with the serum creatinine level. Overall, the two assay methods provided similar pharmacokinetic parameter estimates. However, correlation between the 12-h cyclosporine level determined by RIA and the AUC by HPLC yielded an overestimation of the 24-h AUC determined by HPLC and indicates that therapeutic monitoring of the parent drug in the immediate postoperative period may best be accomplished by HPLC analysis.