Comparative Pharmacokinetics and Renal Effects of Cyclosporin A and Cyclosporin G in Renal Allograft Recipients
Authors: Gruber Scott A. , Gallichio Michael , Rosano Thomas G. , Kaplan Sandra S. , Hughes Stephen E. , Urbauer Diana L. , Singh T. Paul , Lempert Neil , Conti David J. , Stein Daniel S. , Drusano George 
Published: March 2013

Cyclosporin G (CSG) has produced less nephrotoxicity than cyclosporin A (CSA) at equivalent doses in animal models. Conflicting results have been reported concerning differences in the pharmacokinetics of CSA and CSG in preclinical studies, and no data exist regarding the effect of steady‐state oral administration of CSG on renal function in transplant patients or CSG‐induced release of endothelin and nitric oxide (NO) in vivo. The objective of the study was to examine steady‐state pharmacokinetic profiles of adult renal allograft recipients receiving CSA and CSG in relation to concentrations of endothelin‐1 and NO2/NO3 in urine and plasma, creatinine clearance (Clcr), and urinary excretion of N‐acetyl‐β‐D‐glucosaminidase (NAG) 9 months after transplantation. Concentrations of CSA and CSG were measured in whole blood over a 12‐hour dose interval by both a monoclonal and polyclonal fluorescence polarization radioimmunoassay for CSA. A metabolite fraction was defined as the numerical difference between the levels obtained at each time point by both assays. Patient groups were defined as follows: group 1: initial CSA (n = 6); group 2: initial CSG (n = 7); group 3: five of the seven patients in group 2 taking CSG subsequently undergoing conversion to CSA; group 4: the same five patients in group 3 restudied 1 month after 1:1 dosage conversion to CSA; and group 5: CSA groups 1 and 4 combined (n = 11). In group 1, the metabolite fraction accounted for 32% to 54% of the total measurable drug concentration at each time point, whereas in group 2, the metabolite fraction accounted for at most 10% to 15% of the total drug levels measurable by polyclonal fluorescence polarization radioimmunoassay. Although there were no significant differences in any of the mean pharmacokinetic parameters between groups using monoclonal fluorescence polarization radioimmunoassay, the normalized area under the concentration—time curve (NAUC) value was less in four of five patients after conversion from CSG to CSA, with a more variable and delayed time to reach peak concentration (tmax) but equivalent apparent oral clearance (Clpo) values. Clcr was found to change significantly with time in groups 1 and 5 but not in group 2, with CSA producing a more profound and sustained decrease than CSG. Endothelin‐1 and NO2/NO3 levels in plasma and urine remained relatively constant after administration of both CSA and CSG, and there were no significant differences between groups 3 and 4 regarding mean endothelin‐1 and NO2/NO3 concentrations in plasma, urinary release of endothelin‐1 and NO2/NO3, and mean AUC of endothelin‐1 and AUC of NO2/NO3. However, monoclonal NAUC correlated significantly with total urinary endothelin‐1 within CSA groups 1 and 5 but not within CSG group 2. Metabolite NAUC correlated significantly with total urinary NAG within CSA group 1. Although limited by the small number of patients, this study suggests that 1) CSG may produce less of a reduction in Clcr over time after oral administration at steady state than does CSA, and 2) this beneficial effect of CSG may be in part due to decreased intrarenal release of endothelin‐1, as urinary excretion of endothelin‐1 seemed to correlate better with CSA than with CSG exposure.