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 dysfunction after renal transplantation is closely related to the pharmacokinetics of cyclosporin. To clarify the relationship between renal dysfunction and the pharmacokinetics of cyclosporin, we examined the influence of acute renal failure (ARF) on its pharmacokinetics in glycerol‐induced ARF rats. The values of indicators of renal function (serum creatinine, blood urea nitrogen), but not those of indicators of hepatic function, were significantly increased in ARF rats that received glycerol compared with values for control rats. The area under the blood cyclosporin concentration‐time curve after oral administration (AUCpo) were 4.976 ± 0.847 mg hL−1 for ARF rats and 9.684 ± 1.100 mg hL−1 for control rats; AUCpo in ARF was significantly 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 Lh−1 kg−1, respectively, whereas total body clearance in ARF and control rats was 0.151 ± 0.008 and 0.183 ± 0.010 Lh−1 kg−1, respectively. 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 cyclosporin uptake (kuptake) and metabolism (kmetab) in gut tissues were reduced, whereas kuptake and kmetab in liver were increased. Gastric emptying, 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 conclude that reduction of the absorbed fraction of cyclosporin strongly contributes to the decrease in AUCpo in the presence of ARF.