Factors that affect absorption behavior of cyclosporin A in gentamicin-induced acute renal failure in rats

Factors that affect the absorption of cyclosporin A (CsA) were examined in gentamicin-induced acute renal failure (ARF) rats. In ARF rats, the area un der the blood CsA concentration-time curve after oral administration was si gnificantly decreased in comparison with that of control rats; 5.81 +/- 0.5 5 vs 11.30 +/- 1.59 mg h mL(-1)(mean +/- s.e.m.), respectively, and the rel ative bioavailabilities in ARF and control rats after oral administration w ere 15.2% and 43.4%, respectively. The flow rate of bile and the amount of bile acids in ARF rats were markedly decreased to about 61% of control, and 41% of control, respectively. The amount of CsA uptaken into the evened sa c of jejunum, transferred to serosal side, and metabolized in tissues was s ignificantly decreased in ARF rats without verapamil, while with 0.3 mM ver apamil, the amount in ARF rats recovered to the levels of control rats. The absorption clearance of CsA in ARF rats was significantly decreased, howev er it was significantly improved by adding bile or bile acid. Adenosine tri phosphate released from enterocytes in ARF rats was significantly decreased in the presence of 2.0 (1)-M CsA, 0.3 mM verapamil, or both, in comparison with control rats. From these findings, we concluded that a reduction of C sA bioavailability during ARF is caused by depression in bile excretion and renal function-dependent depression of uptake from intestinal tract via ma ybe P-gLycoprotein in enterocytes. They are main two factors that reduce th e absorbed fraction of CsA ill ARF rats.