COMPARATIVE PHARMACOKINETICS AND RENAL EFFECTS OF CYCLOSPORINE-A AND CYCLOSPORINE-G IN RENAL-ALLOGRAFT RECIPIENTS

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 a nd CSG in preclinical studies, and no data exist regarding the effect of steady-state oral administration of CSG on renal function in transp lant patients or CSG-induced release of endothelin and nitric oxide (N O) in vivo. The objective of the study was to examine steady-state pha rmacokinetic profiles of adult renal allograft recipients receiving CS A and CSG in relation to concentrations of endothelin-1 and NO2/NO3 in urine and plasma, creatinine clearance (Cl-cr) and urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) 9 months after transplantatio n. Concentrations of CSA and CSG were measured in whole blood over a 1 2-hour dose interval by both a monoclonal and polyclonal fluorescence polarization radioimmunoassay for CSA. A metabolite fraction was defin ed as the numerical difference between the levels obtained at each tim e point by both assays. Patient groups were defined as follows: group 2: initial CSA (n = 6); group 2: initial CSG (n = 7); group 3: five of the seven patients in group 2 taking CSG subsequently undergoing conv ersion 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 an d 4 combined (n = 11). In group 1, the metabolite fraction accounted f or 32% to 54% of the total measurable drug concentration at each time point, whereas in group 2, the metabolite fraction accounted for at mo st 20% to 15% of the total drug levels measurable by polyclonal fluore scence polarization radioimmunoassay. Although there were no significa nt differences in any of the mean pharmacokinetic parameters between g roups using monoclonal fluorescence polarization radioimmunoassay, the normalized area under the concentration-time curve (NAUC) value was l ess in four of five patients after conversion from CSG to CSA, with a more variable and delayed time to reach peak concentration (t(max)) bu t equivalent apparent oral clearance (Cl-po) values. Cl-cr was found t o change significantly with time in groups 2 and 5 but not in group 2, with CSA producing a more profound and sustained decrease than CSG. E ndothelin-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 endothel in-1 and NO2/NO3 concentrations in plasma, urinary release of endothel in-1 and NO2/NO3, and mean AUC of endothelin-1 and AUC of NO2/NO3. How ever, monoclonal NAUC correlated significantly with total urinary endo thelin-1 within CSA groups 2 and 5 but not within CSG group 2. Metabol ite NAUC correlated significantly with total urinary NAG within CSA gr oup 1. Although limited by the small number of patients, this study su ggests that 1) CSG may produce less of a reduction in Cl-cr over time after oral administration at steady state than does CSA, and 2) this b eneficial effect of CSG may be in part due to decreased intrarenal rel ease of endothelin-1, as urinary excretion of endothelin-2 seemed to c orrelate better with CSA than with CSG exposure.