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 under the blood CsA concentration-time curve after oral administration was significantly decreased in comparison with that of control rats; 5.81 +/- 0.55 vs 11.30 +/- 1.59 mg h mL(-1)(mean+/-s.e.m.), respectively, and the relative bioavailabilities in ARF and control rats after oral administration were 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 sac of jejunum, transferred to serosal side, and metabolized in tissues was significantly decreased in ARF rats without verapamil, while with 0.3 mM verapamil, the amount in ARF rats recovered to the levels of control rats. The absorption clearance of CsA in ARF rats was significantly decreased, however it was significantly improved by adding bile or bile acid. Adenosine triphosphate released from enterocytes in ARF rats was significantly decreased in the presence of 2.0 microM CsA, 0.3 mM verapamil, or both, in comparison with control rats. From these findings, we concluded that a reduction of CsA bioavailability during ARF is caused by depression in bile excretion and renal function-dependent depression of uptake from intestinal tract via maybe P-gLycoprotein in enterocytes. They are main two factors that reduce the absorbed fraction of CsA in ARF rats.
Shibata
N
N
Department of Hospital Pharmacy, Shiga University of Medical Science, Otsu, Japan.
Morimoto
J
J
Hoshino
N
N
Minouchi
T
T
Yamaji
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000042:Absorption; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism / Q000494:pharmacology; D001682:Biological Availability; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004333:Drug Administration Routes; D004347:Drug Interactions; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism; D016231:Fluorescence Polarization Immunoassay; D005839:Gentamicins / Q000633:toxicity*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001647:Bile Acids and Salts; D005839:Gentamicins; D007166:Immunosuppressive Agents; D014665:Vasodilator Agents; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D014700:Verapamil