Influence of glycerol-induced acute renal failure on the pharmacokinetics of cyclosporin in rats

Although it is widely believed that renal dysfunction has no effect on the pharmacokinetics of cyclosporin, many clinical reports suggest that renal d ysfunction after renal transplantation is closely related to the pharmacoki netics of cyclosporin. To clarify the relationship between renal dysfunctio n and the pharmacokinetics of cyclosporin, we examined the influence of acu te renal failure (ARF) on its pharmacokinetics in glycerol-induced ARF rats . The values of indicators of renal function (serum creatinine, blood urea ni trogen), but not those of indicators of hepatic function, were, significant ly increased in ARF rats that received glycerol compared with values for co ntrol rats. The area under the blood cyclosporin concentration-time curve a fter oral administration (AUC(po)) were 4.976 +/- 0.847 mg h L-1 for ARF ra ts and 9.684 +/- 1.100 mg h L-1 for control rats; AUC(po) in ARF was signif icantly reduced in a manner dependent on renal function. The oral clearance of cyclosporin in ARF and control rats was 1.172 +/- 0.207 and 0.544 +/- 0 .062 L h(-1) kg(-1), respectively, whereas total body clearance in ARF and control rats was 0.151 +/- 0.008 and 0.183 +/- 0.010 L h(-1) kg(-1), respec tively. The relative bioavailability of cyclosporin in ARF and control rats was 0.118 and 0.336, respectively. In an in-vitro study using everted sac and liver-slice methods, the apparent first-order rate constants for cyclos porin uptake (k(uptake)) and metabolism (k(metab)) in gut tissues were redu ced, whereas k(uptake) and k(metab) in liver were increased. Gastric emptyi ng, measured by use of paracetamol, was significantly reduced in ARF rats. These results suggest that glycerol-induced ARF results in several changes in the pharmacokinetics of cyclosporin in rats. From these results, we conc lude that reduction of the absorbed fraction of cyclosporin strongly contri butes to the decrease in AUG,, in the presence of ARF.